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. Author manuscript; available in PMC: 2019 May 29.
Published in final edited form as: Neurobiol Aging. 2018 Oct 24;75:223.e1–223.e10. doi: 10.1016/j.neurobiolaging.2018.10.019

A comprehensive screening of copy number variability in dementia with Lewy bodies

Celia Kun-Rodrigues a, Tatiana Orme a,b, Susana Carmona a,b, Dena G Hernandez c,d, Owen A Ross e, John D Eicher f, Claire Shepherd g, Laura Parkkinen h, Lee Darwent b,a, Michael G Heckman i, Sonja W Scholz j,k, Juan C Troncoso l, Olga Pletnikova l, Ted Dawson k, Liana Rosenthal k, Olaf Ansorge h, Jordi Clarimon m, Alberto Lleo m, Estrella Morenas-Rodriguez m, Lorraine Clark n, Lawrence S Honig n, Karen Marder n, Afina Lemstra o, Ekaterina Rogaeva p, Peter St George-Hyslop p,q, Elisabet Londos r, Henrik Zetterberg s, Imelda Barber t, Anne Braae t, Kristelle Brown t, Kevin Morgan t, Claire Troakes u, Safa Al-Sarraj u, Tammaryn Lashley v, Janice Holton v, Yaroslau Compta v,w, Vivianna Van Deerlin x, Geidy E Serrano y, Thomas G Beach y, Suzanne Lesage z, Douglas Galasko aa, Eliezer Masliah bb, Isabel Santana cc, Pau Pastor dd, Monica Diez-Fairen dd, Miquel Aguilar dd, Pentti J Tienari ee, Liisa Myllykangas ff, Minna Oinas gg, Tamas Revesz v, Andrew Lees v, Brad F Boeve hh, Ronald C Petersen hh, Tanis J Ferman ii, Valentina Escott-Price jj, Neill Graff-Radford kk, Nigel J Cairns ll, John C Morris ll, Stuart Pickering-Brown mm, David Mann mm, Glenda M Halliday g,nn, John Hardy a, John Q Trojanowski x, Dennis W Dickson e, Andrew Singleton c, David J Stone oo, Rita Guerreiro a,b,pp, Jose Bras a,b,pp,*
PMCID: PMC6541211  NIHMSID: NIHMS1024346  PMID: 30448004

Abstract

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.

Keywords: Dementia with Lewy bodies, copy number variants, MAPT, SNCA, Genome-wide

1. Introduction

Dementia with Lewy bodies (DLB) is a common and complex form of neurodegenerative disease, and its diagnosis can often be complicated by phenotypic similarities with Alzheimer’s disease (AD), Parkinson’s disease (PD), or even frontotemporal dementia (FTD) (Claassen et al., 2008; Heidebrink, 2002). A more accurate DLB diagnosis is usually obtained by integrating clinical and pathological data from brain autopsy (McKeith et al., 2017).

Genetic studies in DLB have been limited, certainly in comparison with studies on AD or PD, for a number of reasons, most notably because DLB has not been historically considered a genetic disease, given the lack of multiplex kindreds where the disease segregates. In addition, large cohorts of patients are difficult to collect given the frequency of the disease and the rate of misdiagnosis. Despite this, recent studies have conclusively shown that there is a role for genetics in the etiology of DLB (Bras et al., 2014; Guerreiro et al., 2018, 2016; Nalls et al., 2013; Peuralinna et al., 2015). Exome sequencing studies have been performed in small cohorts, as have case studies and Sanger sequencing of specific target genes (Clark et al., 2009; Geiger et al., 2016; Keogh et al., 2016; Koide et al., 2002; Ohtake et al., 2004). Copy number variation (CNV) has not been assessed thus far in DLB, particularly in an unbiased manner and at a genome-wide level.

CNVs have been widely studied in a number of neurological conditions, particularly in developmental phenotypes such as schizophrenia and autism (Glessner et al., 2009; Marshall et al., 2017; McCarthy et al„ 2009) where several microdeletions and microduplications (100–600 kb) have been found to be associated with both diseases (Bassett et al., 2017; Cook et al., 1997; McCarthy et al., 2009; Stefansson et al., 2008; Weiss et al., 2008). In these phenotypes, CNVs play a prominent role in the disease genetic architecture.

Several studies have analyzed CNVs in AD, where APP duplications have been unequivocally shown to cause disease (Delabar et al., 1987; Ghani et al., 2012; Swaminathan et al., 2011, 2012; Zheng et al., 2014, 2015). In PD, pathogenic CNVs are also known to occur in SNCA, PARK2, PINK1, and PARK7 (Bonifati et al„ 2003; Chartier-Harlin et al., 2004; Ibanez et al., 2004; Lesage et al., 2008; Marongiu et al., 2007; Waters and Miller, 1994). Together, these data show that CNVs are an important mutational event in neurological conditions.

Here, we report the first genome-wide analysis of CNVs in DLB in a large cohort of patients, many of which with neuropathology diagnoses of DLB. We performed a case-control association study that was complemented by discovery stage analyses guided by candidate genes and CNVs previously reported as being associated with DLB-related neurodegenerative diseases.

2. Materials and methods

2.1. Sample selection

A total of 1454 patients diagnosed with DLB and of European ancestry were selected for this study. Diagnosis of DLB was made according to clinical or pathological criteria (McKeith et al., 2005), Briefly, these included 298 clinically diagnosed and 1156 neuro-pathologically diagnosed cases. Detailed sample and processing information has been described previously (Guerreiro et al., 2018). Data from 1525 control samples were obtained from The Genetic Architecture of Smoking and Smoking Cessation study (phs000404.vl.pl) publicly available at the database of genotypes and phenotypes (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000404.vl.pl). Supplementary Fig. 1 shows an overview of the study design, different quality control (QC) steps, and analyses performed.

2.2. Genotyping, quality control, and CNV calling

Seven hundred fifty-four DLB samples were genotyped on HumanOmni2.5Exome-8 vl.O.B Illumina arrays, and 700 DLB samples were genotyped using Infinium OmniExpress-24 vl.2.Al Illumina arrays (Illumina, Inc, CA, USA). Control samples were genotyped on HumanOmni2.5–4 vl.D arrays (Illumina, Inc, CA, USA). Intensity files were analyzed using GenomeStudio v2011.1 software (Illumina, Inc, CA, USA) along with the respective manufacturer’s cluster files. QC procedures were performed in GenomeStudio (GS) before CNV analysis as described by Jarick et al. (Jarick et al., 2014). In short, samples with call rates lower than 0.97 were filtered out. SNP statistics were recalculated following visual inspection of B allele frequency (BAF) and log R ratio (LRR) plots. SNPs with GenTrain scores below 0.7 were excluded. Finally, samples with substantial cryptic reiatedness scores (PLHAT > 0.1) were removed, as previously described (Guerreiro et al., 2018).

CNV calls were generated using 2 different algorithms: cnvPartition v2.3.0 (Illumina, Inc) and PennCNV vl.0.4 (Wang et al., 2007). CNV calling based on cnvPartition was performed by GS with default parameters. For PennCNV, probe positions, LRR, and BAF values for samples that passed QC procedures were exported from GS. Population frequency of the B allele (PFB) files was calculated for each array separately. All smoking cessation samples were used to generate CNVs in cnvPartition and PennCNV, but only a subset of the best performing 700 samples was used for the compilation of the PFB file in PennCNV to match the number of samples used for cases. PennCNV GC-model files were then created based on these PFBs. Finally, CNVs were inferred by PennCNV using the hidden Markov model and the GC-model for wave adjustment. Calls for the X chromosome were generated separately. Chromosome Y SNPs were not analyzed.

2.3. CNV quality control and analysis

To improve the quality of CNVs, only calls generated by both algorithms were kept, whereas calls made by a single algorithm or calls of opposing type (e.g., assigned as a deletion by one algorithm and as duplication by the other) were discarded. Adjacent CNVs were merged if the length of the sequence between them was smaller than 50% of the length of the larger CNV (Mok et al., 2016). CNVs were excluded if they were overlapping telomeres, centromeres, known segmental duplications, the immunoglobulin, or T cell receptor loci. Samples having LRR SD > 0.28, BAF drift > 0.002, waviness factor > 0.04, or having more CNV calls than 3*SD + median were excluded (Marshall et al., 2017; Need et al., 2009).

To identify potentially pathogenic CNVs, we analyzed CNVs spanning known genes. We used the database of genomic variants (DGV) (http://dgv.tcag.ca/dgv/app/home, accessed November 2017) to determine the population frequency of CNVs (MacDonald et al., 2014). This information was complemented with the frequency from clinical samples available in DECIPHER v9.18 (https://decipher.sanger.ac.uk/, accessed November 2017).

2.4. Case-control association analysis

Case-control association analysis was implemented using ParseCNV (Glessner et al., 2013). Standard ParseCNV quality metrics were used to filter out low-quality results. CNVs that were genome-wide significant [p-value < 5 × 10‒4 as suggested by (Glessner etal., 2013)] had a minimum length of 50 kb, and passed visual inspection in GS were selected for further analyses.

2.5. Candidate CNVs approach

CNVs previously described in AD (Ghani et al., 2012; Heinzen et al., 2010; Swaminathan et al., 2011, 2012; Zheng et al., 2014, 2015), PD (Bademci et al., 2010; Liu et al., 2013; Mok et al., 2016; Pankratz et al., 2011), and FTD (Gijselinck et al., 2008) were specifically investigated in these data (Supplementary Table 1). This analysis was performed on the complete set of CNV results after QC, disregarding the filters used for the case-control association analysis performed by ParseCNV.

2.6. Candidate genes approach

CNVs located in known AD, PD, FTD, and DLB genes were also assessed (Brás etal., 2015; Guerreiro et al., 2013,2015, 2018; Jansen et al., 2015; Keogh et al., 2016; Koide et al., 2002; Ohtake et al., 2004; Saitoh et al., 1995). Supplementary Table 2 lists all genes studied using this approach.

3. Results

3.1. CNV calling and QC steps

After QC steps at the GS level, a total of 2819 samples (1294 cases and 1525 controls) remained for further analyses. From the 754 DLB samples genotyped with HumanOmni2.5 arrays, 616 (81.7%) samples were kept and from the 2,567,845 probes in this array, 2,496,600 (97.2%) passed QC. Six hundred seventy-eight (96.9%) samples of the 700 samples genotyped with OmniExpress arrays passed QC and from the 713,599 probes available in this chip, 698,680 (97.9%) probes remained. All controls from the Smoking Cessation database had good quality genotypes (call rate > 0.97) and, consequently, no samples were excluded, and 2,390,384 (97.8%) of the 2,443,177 probes were kept.

After combining the results obtained by the 2 CNV calling algorithms (cnvPartition and PennCNV), excluding samples because of their relatedness, and performing the PennCNV QC steps on the LRR and BAF values and number of calls, a final number of 2615 individuals (1187 DLB cases and 1428 control samples) and 80,416 CNVs were analyzed. All samples carrying CNVs were confirmed to be of European/North American ancestry by merging their data with that of 1000 Genomes.

3.2. Case-control association analysis

Of the 494 CNV regions resulting from the ParseCNV analysis, only 5 passed QC checks and were statistically significant (Table 1). Of these, 2 of the regions were not present in our control population or in public databases: the deletion overlapping LAPTM4B (p = 6.29 × 10‒7) and the one overlapping SPAG9-NME1-NME2 (p = 2.72 × 10‒4) (Fig. 1).

Table 1.

Results from the three types of analyses

Genes Location CNV p-value Cases
(Neuroa)		 Controls Cases
frequency		 Controls
frequency		 DGV
frequency		 DECIPHER
frequency
Case-control association analysis
 ADGRG7,TFG chr3:100,357,671–100,439,759 Gain 8.93 × 10−5 21 (18) 13 1.77 × 10−2 9.10 × 10−3 1.43 × 10−2 2.09 × 10−2
 PDZD2 chr5:32101,400–32,106,628 Gain 2.94 × 10−6 14 (12)   0 1.18 × 10−2 0 3.00 × 10−4 1.69 × 10−4
 LAPTM4B chr8:98755,434–98,800,334 Loss 6.29 × 10−7 12 (6)   0 1.01 × 10−2 0 0 0
 MSR1 chr8:15948,235–16,021,468 Loss 1.20 × 10−4 13 (7)   4 1.10 × 10−2 2.80 × 10−3 4.30 × 10−3 7.10 × 10−3
 NME1,NME1-NME2,SPAG9 chr17:49,177,096–49,231,786 Loss 2.72 × 10−4 9 (4)   0 7.58 × 10−3 0 0 0
Candidate CNVs approach
 CSMD1 chr8:4,033,908–4,126,540 Loss 2.89 × 10−2b 3 (2)   0 2.53 × 10−3 0 3.00 × 10−4 0
 DDX11,OVOS2 chr12:31,249,834–31,407,303 Gain 1.41 × 10−2b 4 (2)   0 3.37 × 10−3 0 4.61 × 10−2 0
 CYF1P1,GOLGA8I,NIPA1, chr15:22,750,305–23,272,733 Gain na 5 (5)   8 4.21 × 10−3 5.60 × 10−3 2.50 × 10−3 1.86 × 10−3
 N1PA2,TUBGCP5,WHAMML1
 CHRNA7,OTUD7A chr15:31,932,865–32,515,849 Loss or Gain na 6 (5) 13 5.05 × 10−3 9.10 × 10−3 6.90 × 10−3 8.79 × 10−3
 ASPHD1,BOLA2,C16orf54,CDlPT,CDIPT-AS1, chr16:29,595,483–29,912,902 Gain na 1 (1)   0 8.42 × 10−4 0 0 1.69 × 10−4
 KIF22,MAZ,MVP,PAGR1,PRRT2,QPRT,SEZ6L2,
 SPN,ZG16
Candidate genes approach
 DNAJC6,LEPR,LEPROT chr1:65,854,556–65,955,725 Gain na 1 (0)   1 8.42 × 10−4 7.00 × 10−4 1.72 × 10−4 2.53 × 10−3
 SNCA,SNCA-AS1,GPRIN3,MMRN1,CCSER1 chr4:90,035,549–91,420,358 Gain na 1 (1)   0 8.42 × 10−4 0 6.42 × 10−4 0
 PARK2 chr6:161,601,162–163,259,260 Loss or Gain na 13 (8) 28 1.10 × 10−2 1.96 × 10−2 2.30 × 10−3 1.69 × 10−1
 GABRB3,GABRA5,GABRG3 chr15:26,996,126–27,220,713 Gain na 1 (1)   0 8.42 × 10−4 0 0 1.18 × 10−3
 MAPT,CRHR1,KANSL1,KANSL1-AS1, chr17:43,661,362–44,345,063 Gain na 2 (0)   0 1.68 × 10−3 0 1.03 × 10−4 1.18 × 10−3
 MAPT-ASl,MAPT-IT1,SPPL2C,STH
 APP,ADAMTS1,ADAMTS5,ATP5J,CYYR1, chr21:25,063,840–28,522,487 Gain na 1 (0)   0 8.42 × 10−4 0 0 0
 CYYR1 -AS1,GABPA,JAM2,MRPL39
 CHCHD10,ADORA2A,ADORA2A-AS1, chr22:23,690,325–25,011,417 Gain na 1 (1)   0 8.42 × 10−4 0 6.00 × 10−4 1.18 × 10−3
 C22orfl5,CABIN1,CES5AP1,DDT,DDTL,
 DERL3,DR1CH1,GGT1,GGT5,GSTT1,GSTT1-AS1,
 GSTT2,GSTT2B,GSTTPl,GSTTP2,GUCDl,
 GUSBP11,IGLLl,LRRC75B,MIF,M1F-AS1,
 MMP11,POM121L9P, RGL4,SLC2A11,SMARCB1,
 SNRPD3,SPECC1L,SUSD2,UPB1,VPREB3,
 ZDHHC8P1,ZNF70
 CYP2D6,NDUFA6-AS1 chr22:42,522,613–42,531,210 Loss or Gain na 1 (1)   4 8.42 × 10−4 2.80 × 10−3 2.20 × 10−1 3.00 × 10−2
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All genomic coordinates are for the genome assembly hg19.

a

Neuropathological diagnosis; na–not applicable; p-value—these were calculated including ail cases (not only neuropathologically confirmed cases),

b

p-values resulting from the case-control association analysis.

Fig. 1.

Fig. 1.

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Schematic representation of statistically significant CNVs resulting from the case–control analysis that were not found in controls or publicy available databases. CVNs overlappig LAPTM4B in A; and SPAG9/NME1 in B.Known transcripts are represented at the bottom of each panel. Passing QC SNPs used for the CNV calling are depicted by color according to the genotyping arrary (red: OmniExpress, blue: Omni2.5 M, green: Omni2.5 M for controls). CNVs (duplications) are depicted as bars above the genes. The gray shadow area represents the associated region that is genome-wide significant.

3.3. Candidate CNVs approach

Five CNVs previously associated with DLB-related neurodegenerative diseases were found in DLB patients (Table 1). Two of these were present in the control group with a higher frequency than in the patient group, and the remaining 3 are described in public databases and are detailed next. The duplication identified on chromosome 12 overlapping DDXU and OVOS2 has a frequency 10-fold higher in DGV than in the DLB cohort. The 16pl 1.2 microduplication found in one DLB patient has a frequency of 1.69 × 10‒4 in the DECIPHER database but does not occur in any control samples or in the DGV database. One of the CNVs that was previously significantly associated with AD locates at chr8:2,792,874–4,852,328 and overlaps CSMD1 (Swaminathan et al., 2011). CSMD1 has frequent deletions and duplications spanning the whole gene as reported in DGV. Our results agree with this: at this locus, we identified over 100 deletions in cases and controls. One region in the gene has a deletion in 3 cases and in no controls and this CNV showed a suggestive significance in our DLB case-control association analysis. Therefore, we only report this shorter region in Table 1.

3.4. Candidate genes approach

We investigated CNVs in genes known to be associated with diseases that are related to DLB (Supplementary Table 2) and identified a total of 8 CNVs (Table 1). These included one duplication in APP occurring in a clinically diagnosed case. This large duplication is not present in the databases or in the control cohort. Two DLB subjects were found to carry duplications spanning MAPT, and one neuropathologically diagnosed patient was found to cany a SNCA duplication (Fig. 2). PARK2 was found to have many copy number losses and gains in controls (n = 28) and cases (n = 13) but none were homozygous. A duplication including CHCHD10 was also identified in a neuropathologically diagnosed DLB patient. No CNVs were identified in CBA, the gene presenting the strongest association with DLB.

Fig. 2.

Fig. 2.

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Duplication identified at the SNCA locus. Log R ratio and B alleie frequency plots of the CNV identified in the SNCA locus. Each point represents an SNP according to location in chromosome 4 (position on X axis). The genomic duplication is indicated by an increase in log R ratio and B allele frequency clusters outside the expected values of 1 (B/B), 0.5 (A/B), and 0 (A/A). Genes are represented at the bottom as black bars. SNPs inside the CNV region are represented in red. SNPs outside the CNV region are represented in blue, and SNPs in SNCA are represented in green.

4. Discussion

We performed a systematic analysis of CNVs in a large cohort of DLB patients using 3 main approaches. The first of these approaches was a case-control association analysis, which resulted in 5 significant CNV regions that have not been previously described as associated with the disease. The most significant result from this analysis was a deletion spanning a lysosome-associated transmembrane protein, LAPTM4B. Intraneuronal alpha-synuclein clearance likely occurs through a variety of mechanisms to maintain protein homeostasis. However, recent data have highlighted the importance of lysosomal pathways for degradation of this protein (Webb et al., 2003). Interestingly, a member of the same protein family, LAPTM5, was one of the top hits for incidental DLB in a recent network analysis study (Santpere et al., 2018). Although we cannot directly link this CNV to the development of DLB in these cases, it is interesting that a lysosomal enzyme is the top hit in our association analysis, given the prominent role of the lysosome in Lewy body diseases. In fact, a strong GWAS hit for DLB is GBA, a gene involved in lysosomal lipid storage disorders.

Also associated with DLB and absent from publicly available databases was a deletion overlapping theNME1 locus.NME1 is involved in purine metabolism, which has been reported to be disrupted in AD, PD, and Creutzfeldt—Jakob disease. NME1 mRNA was also found to be reduced in these diseases (Ansoleaga etal.,2015,2016; Garcia-Esparcia et al., 2015). Here, we identified a deletion at the 3’-end of NME1, which could be consistent with a reduced expression of the gene in DLB, although this was not tested in the present study.

Using a candidate gene approach where we analyzed genes known to have a role in DLB and DLB-related diseases, we identified several CNVs of potential interest. The hallmark of DLB at autopsy is the accumulation of alpha-synuclein protein within neurons and their processes, termed Lewy bodies and Lewy neurites (Spillantini et al., 1997). Variants in the SNCA gene, which encodes alpha-synuclein, have been previously associated with the risk of developing DLB (Bras et al., 2014; Guerreiro et al., 2018). In addition to point mutations, CNVs including SNCA are known to cause PD, and over the past years, evidence has suggested that this gene may also be duplicated in DLB. Nishioka et al. identified a PD family with a duplication spanning all of SNCA and MMRN1 where the proband was later neuropathologically diagnosed as DLB (Nishioka et al., 2006; Obi et al., 2008). Four neuropathologically diagnosed DLB cases presented a large duplication from DSPP to PDLIM5 including SNCA, 3 of these were heterozygous and 1 was homozygous (Ikeuchi et al., 2008). A duplication in SNCA was also described in a probable DLB patient in a study with 99 cases (Meeus et al., 2012). Here, we add to this body of evidence, by identifying another patient neuropathologically diagnosed with DLB carrying a SNCA duplication. In our DLB cohort, this duplication shows a similar frequency to that provided by DGV. However, the frequency reported in DGV results from 2 entries in that database. When looking in more detail at these 2 entries, they are actually duplicated entries from the same Human Genome Diversity Project (HGDP) sample from Cambodia (HGDP00721). Given that information for each HGDP samples is limited to sex of the individual, population, and geographic origin, it is possible this sample originated from a PD or DLB patient or from an asymptomatic carrier, as these have previously been reported, with SNCA multiplications having particularly low penetrance levels in Asian populations (Ahn et al., 2008; Nishioka et al., 2006). It is also possible the duplication reported is an artifact caused by the creation or passage of the lymphoblast cell lines used to extract DNA (Simon-Sanchez et al., 2007).

We also identified one heterozygous duplication encompassing CHCHD10, a gene previously shown to cause FTD and/or amyotrophic lateral sclerosis (Zhang et al., 2015). However, given that disease-associated CHCHD10 mutations are loss of function (Perrone et al., 2017), it is not clear whether a duplication of the gene would be pathogenic.

GABRB3 is a gamma-aminobutyric acid (GABA) receptor that was reported to be associated with DLB in a recent GWAS but did not survive independent replication (Guerreiro et al., 2018). However, loss of GABA receptors could underlie the typical visual hallucinations in DLB (Khundakar et al., 2016), and because of this, we specifically looked at CNVs in GABRB3 and identified a duplication in one case. Given the GWAS results previously mentioned, the CNV detected here and the fact that GABA receptor neurotransmission is altered in DLB (Santpere et al., 2018), it is tempting to speculate that genetic variability in GABA receptors may, in fact, modulate risk for DLB.

We identified 2 clinically diagnosed DLB samples with MAPT duplications (Fig. 3). MAPT was not found to be significantly associated with DLB in recent GWAS (Bras et al., 2014; Guerreiro et al., 2018), but the MAPT HI haptotype was previously described as a possible risk factor for DLB (Cervera-Carles et al., 2016; Labbé et al., 2016) and is a well-known genetic risk factor for PD. Previous studies of small cohorts of FTD patients have not revealed causative MAPT duplications (Lladó et al., 2007; Skoglund et al„ 2009) but the screening of French FTD patients including multiplex families led to the identification of a heterozygous partial deletion of MAPT (Rovelet-Lecrux et al., 2009) and a 17q21.31 microduplication in an atypical FTD case (Rovelet-Lecrux et al., 2010). More recently, MAPT duplications were shown to increase expression of MAPT mRNA and were found to cause tangle pathology without Aβ deposition in probable AD patients (Le Guennec et al., 2017).

Fig. 3.

Fig. 3.

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Duplications identified at the MAPT locus. Log R ratio and B allele frequency plots of the CNVs identified at the MAPT locus in 2 clinically diagnosed DLB cases. Each point represents an SNP according to location in chromosome 17 (position on X axis). The genomic duplication is indicated by an increase in log R ratio and B allele frequency clusters outside the expected values of 1 (B/B), 0.5 (A/B), and 0 (A/A). Genes are represented at the bottom as black bars. SNPs inside the CNV regions are represented in red, SNPs outside the CNV regions are represented in blue, and SNPs in MAPT are represented in green.

PARK2 homozygous CNVs are the most common copy number cause of PD, accounting for more than 50% of all pathogenic mutations in the gene and more frequently affecting the region between exons 2 and 7 (Hedrich et al., 2004; Kim et al., 2012). Our results showed no significant differences in the frequency of heterozygous CNVs overlapping PARK2 between DLB cases and controls, similar to the findings by Kay et al. in PD (Kay et al., 2010). In addition, we did not find any homozygous PARK2 CNVs suggesting that CNVs in this gene do not play a causative role in DLB.

APP duplications are known to cause AD (Delabar et al., 1987; Ghani et al., 2012; Swaminathan et al., 2011, 2012; Zheng et al., 2014, 2015). The sample carrying an APP duplication in our cohort has a clinical diagnosis of DLB without neuropathological confirmation; it is therefore possible that this is an AD case misdiagnosed as DLB. However, there have been reports in the literature of DLB cases associated with APP duplications. For example, in a French family presenting with a diverse phenotype, APP duplication was associated with DLB confirmed by neuropathological findings (Guyant-Marechal et al, 2008). Similarly, one case with Lewy body—variant AD was reported in a multigenerational dementia family from the Netherlands (Sleegers et al., 2006). DLB cases frequently present Aβ pathology at autopsy (Hepp et al., 2016), and it has been suggested that Aβ accumulation can trigger Lewy body disease (Masliah et al, 2001).

There are 2 main limitations in this study: first, this is a relatively small-sized cohort, which means we cannot confidently assess associations of CNVs with low effect sizes on disease; second, we did not perform independent replication of these findings, which precludes us from establishing definite associations or causes of disease. Despite these limitations, we report on the first systematic analysis of CNVs in a large cohort of DLB patients, using well-established analytical practices. We identified potential disease causing CNVs as well as potential novel candidate genes for DLB. Despite this, our results suggest that it is unlikely that CNVs play a significant role in the pathogenesis of DLB.

Supplementary Material

Suppl1

Acknowledgements

RG and JB work is funded by fellowships from the Alzheimer’s Society. TO work is funded by a scholarship from The Lewy Body Society. For the neuropathologically confirmed samples from Australia, tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales, and GMH is funded by an NHMRC senior principal research fellowship. The authors thank the South West Dementia Brain Bank (SWDBB) for providing brain tissue for this study. The SWDBB is supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly), Brains for Dementia Research, and the Medical Research Council. The authors acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the N1HR Oxford Biomedical Research Center. The brain samples and/or bio samples were obtained from The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl). All materials have been collected from donors for or from whom a written informed consent for a brain autopsy, and the use of the material and clinical information for research purposes had been obtained by the NBB. This study was also partially funded by the Wellcome Trust, and the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (PSGH). Work from YC was supported by the CERCA Program/Generalitat de Catalunya, Barcelona, Catalonia, Spain. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson’s Disease Foundation, and NIH grants NS060113 (LC), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I.R. Burke), and UL1TR000040 (P.I.H. Ginsberg). OAR is supported by the Michael J. Fox Foundation for Parkinson’s Research, N1NDS R01# NS078086. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson’s Disease Research Center of Excellence (N1NDS P50 #NS072187) and is supported by The Little Family Foundation and by the Mangurian Foundation Program for Lewy Body Dementia research and the Alzheimer Disease Research Center (P50 AG016547). The work from the Mayo Clinic Rochester is supported by the National Institute on Aging (P50 AG016574 and U01 AG006786). This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology, where TL is funded by an ARUK senior fellowship. Some of the tissue samples studied were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer’s Society and ARUK). This research was supported in part by both the NIHR UCLH Biomedical Research Center and the Queen Square Dementia Biomedical Research Unit. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951–12. The University of Pennsylvania case collection is funded by the Penn Alzheimer’s Disease Core Center (AG10124) and the Penn Morris K. Udall Parkinson’s Disease Research Center (NS053488). Tissue samples from UCSD are supported by NIH grant AG05131. The authors thank the brain bank GIE NeuroCFB, the French program “Investissements d’avenir” (ANR-10-IAIHU-06). PJT and LM are supported by the Helsinki University Central Hospital and Sigrid juselius Foundation and the Finnish Academy. This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (ER). The authors acknowledge the contribution of data from Genetic Architecture of Smoking and Smoking Cessation accessed through dbGAP. Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274–01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; POf CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). This work was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke; project ZIA NS003154). Tissue samples for genotyping were provided by the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson’s Disease Research (NIH P50 NS38377) and the Johns Hopkins Alzheimer Disease Research Center (NIH P50 AG05146). This study was supported by grants from the National Institutes of Health, the Canadian Institute for Health Research, and the Krembil Foundation. Additional support was provided by the Babcock Memorial Trust and by the Barbara and Neal Henschel Charitable Foundation.

Footnotes

5.Disclosure

The authors have no actual or potential conflicts of interest.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.neurobiolaging.2018.10.019.

References

  1. Ahn T-B, Kim SY, Kim JY, Park S-S, Lee DS, Min HJ, Kim YK, Kim SE, Kim J-M, Kim HJ, Cho J, Jeon BS, 2008. alpha-Synuclein gene duplication is present in sporadic Parkinson disease. Neurology 70, 43–49. [DOI] [PubMed] [Google Scholar]
  2. Ansoleaga B, Garcia-Esparcia P, Llorens F, Hernández-Ortega K, Carmona Tech M., Del Rio J. Antonio, Zerr I, Ferrer I, 2016. Altered Mitochondria, protein Synthesis Machinery, and Purine Metabolism are Molecular Contributors to the Pathogenesis of Creutzfeldt-Jakob Disease. J. Neuropathol. Exp. Neurol, 10.1093/jnen/nlw048. [DOI] [PubMed] [Google Scholar]
  3. Ansoleaga B, Jové M, Schlüter A, Garcia-Esparcia P, Moreno J, Pujol A, Pamplona R, Portero-Otín M, Ferrer I, 2015. Deregulation of purine metabolism in Alzheimer’s disease. Neurobiol. Aging 36, 68–80. [DOI] [PubMed] [Google Scholar]
  4. Bademci G, Edwards TL, Torres AL, Scott WK, Züchner S, Martin ER, Vance JM, Wang L, 2010. A rare novel deletion of the tyrosine hydroxylase gene in Parkinson disease. Hum. Mutat. 31, E1767–E1771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bassett AS. Lowther C, Merico D, Costain G, Chow EWC, van Amelsvoort T, McDonald-McGinn D, Gur RE, Swillen A, Van den Bree M, Murphy K, Gothelf D, Bearden CE, Eliez S, Kates W, Philip N, Sashi V, Campbell L, Vorstman J, Cubells J, Repetto GM, Simon T, Boot E, Heung T, Evers R, Vingerhoets C, van Duin E, Zackai E, Vergaelen E, Devriendt K, Vermeesch JR, Owen M, Murphy C, Michaelovosky E, Kushan L, Schneider M, Fremont W, Busa T, Hooper S, McCabe K, Duijff S, Isaev K, Pellecchia G, Wei J, Gazzellone MJ, Scherer SW, Emanuel BS, Guo T, Morrow BE, Marshall CR, International 22qll.2DS Brain and Behavior Consortium, 2017. Rare genome-wide copy number variation and expression of schizophrenia in 22qll.2 deletion syndrome. Am. j. Psychiatry 174,1054–1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bonifati V, Rizzu P, van Baren MJ, Schaap O , Breedveld GJ, Krieger E, Dekker MCJ, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P, 2003. Mutations in the DJ-1 gene associated with autosomal recessive earlyonset parkinsonism. Science 299, 256–259. [DOI] [PubMed] [Google Scholar]
  7. Bras J, Guerreiro R, Darwent L, Parkkinen L, Ansorge O, Escott-Price V, Hernandez DG, Nalls MA, Clark LN, Honig LS, Marder K, Van Der Flier WM, Lemstra A, Scheltens P, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Ortega-Cubero S, Pastor P, Ferman TJ, Graff-Radford NR, Ross OA, Barber L, Braae A, Brown K, Morgan K, Maetzler W, Berg D, Troakes C, Al-Sarraj S, Lashley T, Compta Y, Revesz T, Lees A, Cairns N, Halliday GM, Mann D, Pickering-Brown S, Dickson DW, Singleton A, Hardy J, 2014. Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum. Mol. Genet. 23, 6139–6146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brás J , Guerreiro R, Hardy J. 2015. SnapShot: genetics of Parkinson’s disease. Cell 160, 570–570.el. [DOI] [PubMed] [Google Scholar]
  9. Cervera-Carles L, Pagonabarraga J. Pascual-Sedano B, Pastor P, Campolongo A, Fortea J, Blesa R, Alcolea D, Morenas-Rodríguez E, Sala L, Lleó A, Kulisevsky J, Clarimón J, 2016. Copy number variation analysis of the 17q21.31 region and its role in neurodegenerative diseases. Am. J. Med. Genet. B Neuropsychiatr. Genet. 171B, 175–180. [DOI] [PubMed] [Google Scholar]
  10. Chartier-Harlin M-C, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J. Hulihan M, Waucquier N, Defebvre L, Amouyel P, Farrer M, Destée A, 2004. Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364,1167–1169. [DOI] [PubMed] [Google Scholar]
  11. Claassen DO, Parisi JE, Giannini C, Boeve BF, Dickson DW, Josephs KA, 2008. Frontotemporal dementia mimicking dementia with Lewy bodies. Cogn. Behav. Neurol. 21,157–163. [DOI] [PubMed] [Google Scholar]
  12. Clark LN, Kartsaklis LA, Wolf Gilbert R., Dorado B, Ross BM, Kisselev S, Verbitsky M, Mejia-Santana H, Cote LJ, Andrews H, Vonsattel J-P, Fahn S , Mayeux R, Honig LS, Marder K, 2009. Association of glucocerebrosidase mutations with dementia with lewy bodies. Arch. Neurol. 66, 578–583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cook EH Jr., Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E, 1997. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am. J. Hum. Genet. 60, 928–934. [PMC free article] [PubMed] [Google Scholar]
  14. Delabar JM, Goldgaber D. Lamour Y, Nicole A, Huret JL, de Grouchy J, Brown P, Cajdusek DC, Sinet PM, 1987. Beta amyloid gene duplication in Alzheimer’s disease and karyotypically normal Down syndrome. Science 235, 1390–1392. [DOI] [PubMed] [Google Scholar]
  15. Garcia-Esparcia P, Hemández-Ortega K, Ansoleaga B, Carmona M, Ferrer L, 2015. Purine metabolism gene deregulation in Parkinson’s disease. Neuropathol. Appl. Neurobiol. 41, 926–940. [DOI] [PubMed] [Google Scholar]
  16. Geiger JT, Ding J, Crain B, Pletnikova O, Letson C, Dawson TM, Rosenthal LS, Pantelyat A, Gibbs JR, Albert MS, Hernandez DG, Hillis AE, Stone DJ, Singleton AB, North American Brain Expression Consortium, Hardy JA, Troncoso JC, Scholz SW, 2016. Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. Neurobiol. Dis. 94, 55–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ghani M, Pinto D, Lee JH, Grinberg Y, Sato C, Moreno D, Scherer SW, Mayeux R, St George-Hyslop P, Rogaeva E. 2012. Genome-wide survey of large rare copy number variants in Alzheimer’s disease among Caribbean his-panics. G3 (Bethesda) 2, 71–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gijselinck I, van der Zee J, Engelborghs S, Goossens D, Peeters K, Mattheijssens M, Corsmit E, Dei-Favero J, De Deyn PP, Van Broeckhoven C, Cruts M, 2008. Progranulin locus deletion in frontotemporal dementia. Hum. Mutat. 29, 53–58. [DOI] [PubMed] [Google Scholar]
  19. Glessner JT, Li J. Hakonarson H. 2013. ParseCNV integrative copy number variation association software with quality tracking. Nucleic Acids Res. 41, e64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, lmielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PMA, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J , Meyer KJ, Anagnostou E, Sakurai T, Game RM. Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nürnberger JI. Coon H, Sutcliffe JS, Minshew NJ, Grant SFA, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H, 2009. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569–573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Guerreiro R, Brás j., Hardy J, 2015. SnapShot: genetics of ALS and FTD. Cell 160, 798.el. [DOI] [PubMed] [Google Scholar]
  22. Guerreiro R, Brás J, Hardy J, 2013. SnapShot: genetics of Alzheimer’s disease. Cell 155 968–968.el. [DOI] [PubMed] [Google Scholar]
  23. Guerreiro R, Escott-Price V, Darwent L, Parkkinen L, Ansorge O, Hernandez DG, Nalls MA, Clark L, Honig L, Marder K, van der Flier W, Holstege H, Louwersheimer E, Lemstra A, Scheltens P, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Ortega-Cubero S, Pastor P, Ferman TJ, Graff-Radford NR, Ross OA, Barber I, Braae A, Brown K, Morgan K, Maetzler W, Berg D, Troakes C, Al-Sarraj S, Lashley T, Compta Y, Revesz T, Lees A, Caims NJ, Halliday GM, Mann D, Pickering-Brown S, Powell J, Lunnon K, Lupton MK, International Parkinson’s Disease Genomics Consortium (1PDGC), Dickson D, Hardy J, Singleton A, Bras J, 2016. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson’s and Alzheimer’s diseases. Neurobiol. Aging 38, 214.e7–214.el0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD, Shepherd CE, Parkkinen L, Darwent L, Heckman MG, Scholz SW, Troncoso JC, Pletnikova O, Ansorge O, Clarimon j., Lleo A, Morenas-Rodriguez E, Clark L, Honig LS, Marder K, Lemstra A, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber L, Braae A, Brown K, Morgan K, Troakes C , Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Serrano GE, Beach TG, Lesage S, Galasko D, Masliah E, Santana L, Pastor P, Diez-Fairen M, Aguilar M, Tienari PJ, Myllykangas L, Oinas M , Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Escott-Price V, Graff-Radford N, Caims NJ, Morris JC, Pickering-Brown S, Mann D, Halliday GM, Hardy J, Trojanowski JQ, Dickson DW, Singleton A, Stone DJ, Bras J, 2018. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 17, 64–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Guyant-Marechal I, Berger E, Laquerriére A, Rovelet-Lecrux A, Viennet G, Frebourg T, Rumbach L, Campion D. Hannequin D, 2008. Intrafamilial diversity of phenotype associated with app duplication. Neurology 71, 1925–1926. [DOI] [PubMed] [Google Scholar]
  26. Hedrich K, Eskelson C, Wilmot B, Marder K, Harris J, Garrels J, Meija-Santana H, Vieregge P, Jacobs H, Bressman SB, Lang AE, Kann M, Abbruzzese G, Martinelli P, Schwinger E, Ozelius LJ, Pramstaller PP, Klein C, Kramer P, 2004. Distribution, type, and origin of Parkin mutations: review and case studies. Mov. Disord. 19, 1146–1157. [DOI] [PubMed] [Google Scholar]
  27. Heidebrink JL, 2002. Is dementia with Lewy bodies the second most common cause of dementia? J. Geriatr. Psychiatry Neurol. 15,182–187. [DOI] [PubMed] [Google Scholar]
  28. Heinzen EL, Need AC, Hayden KM, Chiba-Falek O, Roses AD, Strittmatter WJ, Burke JR. Hulette CM, Welsh-Bohmer KA, Goldstein DB, 2010. Genome-wide scan of copy number variation in late-onset Alzheimer’s disease. J. Alzheimers. Dis. 19, 69–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hepp DH, Vergoossen DLE, Huisman E, Lemstra AW, Netherlands Brain Bank, Berendse HW, Rozemuller AJ, Foncke EMJ, van de Berg WDJ, 2016. Distribution and Load of amyloid-β pathology in Parkinson disease and dementia with lewy bodies. J. Neuropathol. Exp. Neurol. 75, 936–945. [DOI] [PubMed] [Google Scholar]
  30. Ibáñez P, Bonnet AM, Débarges B, Lohmann E, Tison F, Poliak P, Agid Y, Dürr A. Brice A, 2004. Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet 364, 1169–1171. [DOI] [PubMed] [Google Scholar]
  31. Ikeuchi T, Kakita A, Shiga A. Kasuga K. Kaneko H. Tan C-F, Idezuka J, Wakabayashi K, Onodera O, Iwatsubo T, Nishizawa M, Takahashi H, Ishikawa A, 2008. Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. Arch. Neurol. 65, 514–519. [DOI] [PubMed] [Google Scholar]
  32. Jansen IE, Bras JM, Lesage S, Schulte C, Gibbs JR, Nalls MA. Brice A, Wood NW, Morris H, Hardy JA, Singleton AB, Gasser T, Heutink P, Sharma M. IPDGC. 2015. CHCHD2 and Parkinson’s disease. Lancet Neurol. 14, 678–679. [DOI] [PubMed] [Google Scholar]
  33. Jarick L, Volckmar AL, Pütter C, Pechlivanis S, Nguyen TT, Dauvermann MR , Beck S, Albayrak Ö, Scherag S, Gilsbach S, Cichon S, Hoffmann P, Degenhardt F, Nöthen MM, Schreiber S, Wichmann HE, Jöckei K-H, Heinrich J, Tiesler CMT, Faraone SV, Walitza S, Sinzig J, Freitag C, Meyer J, Herpertz-Dahlmann B, Lehmkuhl G, Renner TJ, Warnke A, Romanos M, Lesch KP, Reif A, Schimmelmann BC, Hebebrand J, Scherag A, Hinney A, 2014. Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder. Mol. Psychiatty 19,115–121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kay DM, Stevens CF., Hamza TH, Montimurro JS, Zabetian CP, Factor SA, Samii A, Griffith A, Roberts JW, Molho ES, Higgins DS, Gancher S, Moses L, Zareparsi S, Poorkaj P, Bird T, Nutt J, Schellenberg GD, Payami H, 2010. A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2. Neurology 75,1189–1194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Keogh MJ, Kurzawa-Akanbi M, Griffin H, Douroudis K, Ayers KL, Hussein RI, Hudson G, Pyle A, Cordeil HJ, Attems J, McKeith IG, O’Brien JT, Burn DJ, Morris CM, Thomas AJ, Chinnery PF, 2016. Exome sequencing in dementia with Lewy bodies. Transl. Psychiatry 6, e728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Khundakar AA, Hanson PS, Erskine D, Lax NZ, Roscamp J, Karyka E, Tsefou E, Singh P, Cockell SJ, Gribben A, Ramsay L, Blain PG, Mosimann UP, Lett DJ, Elstner M, Turnbull DM, Xiang CC, Brownstein MJ, O’Brien JT, Taylor j-P., Attems J, Thomas AJ, McKeith LG, Morris CM, 2016. Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations. Acta Neuropathol. Commun. 4, 66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kim SY, Seong MW, Jeon BS, Kim SY, Ko HS, Kim JY, Park SS, 2012. Phase analysis identifies compound heterozygous deletions of the PARK2 gene in patients with early-onset Parkinson disease. Clin. Genet. 82, 77–82. [DOI] [PubMed] [Google Scholar]
  38. Koide T, Ohtake H, Nakajima T, Furukawa H, Sakai K, Kamei H, Makifuchi T , Fukuhara N, 2002. A patient with dementia with Lewy bodies and codon 232 mutation of PRNP. Neurology 59, 1619–1621. [DOI] [PubMed] [Google Scholar]
  39. Labbé C, Heckman MG, Lorenzo-Betancor O, Soto-Ortolaza AI, Walton RL, Murray ME, Allen M, Uitti RJ, Wszolek ZK, Smith GE, Kantarci K, Knopman DS, Lowe VJ, Jack CR Jr., Ertekin-Taner N. Hassan A, Savica R, Petersen RC, Parisi JE, Maraganore DM, Graff-Radford NR, Ferman TJ, Boeve BF, Dickson DW, Ross OA, 2016. MAPT haplotype H1G is associated with increased risk of dementia with Lewy bodies. Alzheimers. Dement. 12, 1297–1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Le Guennec K, Quenez O, Nicolas G, Walion D, Rousseau S, Richard A-C , Alexander J, Paschou P, Charbonnier C, Bellenguez C, Grenier-Boley B, Lechner D, Bihoreau M-T, Olaso R, Boland A, Meyer V, Deleuze J-F, Amouyel P, Munter HM, Bourque G, Lathrop M, Frebourg T, Redon R, Letenneur L, Dartigues J-F, Martinaud O, Kalev O, Mehrabian S, Traykov L, Strobel T, Le Ber L, Caroppo P, Epelbaum S, Jonveaux T, Pasquier F, Rollin-Sillaire A, Génin E, Guyant-Maréchal L, Kovacs GG, Lambert J-C, Hannequin D, Campion D, Rovelet-Lecrux A, 2017. 17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression. Mol. Psychiatry 22,1119–1125. [DOI] [PubMed] [Google Scholar]
  41. Lesage S, Lohmann E. Tison F. Dürif F. Dürr A. Brice A. French Parkinson’s Disease Genetics Study Group, 2008. Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls. J. Med. Genet. 45, 43–46. [DOI] [PubMed] [Google Scholar]
  42. Liu X, Cheng R, Ye X, Verbitsky M, Kisseiev S, Mejia-Santana H, Louis E, Cote L, Andrews H, Waters C, Ford B. Fahn S, Marder K, Lee J, Clark L, 2013. Increased rate of sporadic and recurrent rare genic copy number variants in Parkinson’s disease among Ashkenazi Jews. Mol. Genet. Genomic Med. 1142–154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Lladö A, Rodríguez-Santiago B, Antonell A, Sánchez-Valle R, Molinuevo JL, Reñé R, Pérez-Jurado LA., 2007. MAPT gene duplications are not a cause of frontotemporal lobar degeneration. Neurosci. Lett. 424, 61–65. [DOI] [PubMed] [Google Scholar]
  44. MacDonald JR, Ziman R, Yuen RKC, Feuk L, Scherer SW, 2014. The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 42, D986–D992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Marongiu R, Brancati F, Antonini A, lalongo T, Ceccarini C, Scarciolla O, Capalbo A, Benti R, Pezzoli G, Dallapiccola B, Goldwurm S, Valente EM, 2007. Whole gene deletion and splicing mutations expand the PINK1 genotypic spectrum. Hum. Mutat. 28, 98. [DOI] [PubMed] [Google Scholar]
  46. Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, Antaki D, Shetty A, Holmans PA, Pinto D, Gujral M, Brandler WM, Malhotra D, Wang Z, Fajarado KVF, Maile MS, Ripke S, Agartz L, Albus M, Alexander M, Amin F, Atkins J, Bacanu SA, Belliveau RA Jr., Bergen SE, Bertalan M, Bevilacqua E, Bigdeli TB, Black DW, Bruggeman R, Buccola NG, Buckner RL, Bulik-Sullivan B, Byerley W, Cahn W, Cai G, Cairns MJ, Campion D, Cantor RM, Carr VJ, Carrera N, Catts SV, Chambert KD, Cheng W, Cloninger CR, Cohen D, Cormican P, Craddock N , Crespo-Facorro B, Crowley j.j., Curtis D, Davidson M, Davis KL, Degenhardt F, Del Favero J, DeLisi LE, Dikeos D, Dinan T, Djurovic S, Donohoe G, Drapeau E, Duan J, Dudbridge F, Eichhammer P, Eriksson J, Escott-Price V, Essioux L, Fanous AH, Farh K-H, Farrell MS, Frank J, Franke L, Freedman R, Freimer NB, Friedman JI, Forstner AJ, Fromer M, Genovese G, Georgieva L, Gershon ES, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JL, Gratten J, de Haan L, Hamshere ML, Hansen M, Hansen T, Haroutunian V, Hartmann AM, Henskens FA, Herms S, Hirschhorn JN, Hoffmann P, Hofman A, Huang H, Ikeda M, Joa L, Kähler AK, Kahn RS, Kalaydjieva L, Karjalainen J. Kavanagh D. Keller MC, Kelly BJ, Kennedy JL, Kim Y, Knowles JA, Konte B. Laurent C , Lee P, Lee SH, Legge SE, Lerer B, Levy DL, Liang KY, Lieberman J, Lönnqvist J, Loughland CM, Magnusson PKE, Maher BS, Maier W, Mallet J„ Mattheisen M, Mattingsdal M, McCarley RW, McDonald C, McIntosh AM, Meier S, Meijer CJ. Melle I. Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V. Mokrab Y, Morris DW, Müller-Myhsok B, Murphy KC, Murray RM, Myin-Germeys L, Nenadic L, Nertney DA, Nestadt G, Nicodemus KK, Nisenbaum L, Nordin A, O’Callaghan E, O’Dushlaine C, Oh S-Y, Olincy A, Olsen L, O’Neill FA, Van Os J, Pantelis C, Papadimitriou GN, Parkhomenko E, Pato MT, Paunio T, Psychosis Endo-phenotypes International Consortium, Perkins DO, Pers TH, Pietiläinen O, Pimm J, Pocklington AJ, Powell J, Price A, Pulver AE, Purcell SM, Quested D, Rasmussen HB, Reichenberg A, Reimers MA, Richards AL, Roffman JL, Roussos P, Ruderfer DM, Salomaa V, Sanders AR, Savitz A, Schall U, Schulze TG, Schwab SG, Scolnick EM, Scott RJ, Seidman LJ, Shi J, Silverman JM, Smoller JW, Söderman E, Spencer CCA, Stahl EA, Strengman E, Strohmaier J, Stroup TS, Suvisaari J, Svrakic DM, Szatkiewicz JP, Thirumalai S, Tooney PA, Veijola J, Visscher PM, Waddington J, Walsh D, Webb BT, Weiser M, Wildenauer DB, Williams NM, Williams S, Witt SH. Wolen AR, Wormley BK, Wray NR, Wu JQ, Zai CC, Adolfsson R. Andreassen OA, Blackwood DHR, Bramon E, Buxbaum JD, Cichon S, Collier DA, Corvin A, Daly MJ, Darvasi A, Domenici E„ Esko T, Gejman PV, Gill M, Gurling H, Hultman CM, Iwata N, Jablensky AV, Jönsson EG, Kendler KS, Kirov G, Knight J, Levinson DF, Li QS, McCarroll SA, McQuillin A, Moran JL, Mowry BJ, Nöthen MM, Ophoff RA, Owen MJ, Palotie A, Pato CN, Petryshen TL, Posthuma D, Rietschel M, Riley BP, Rujescu D, Sklar P, St Clair D. Walters JTR, Werge T, Sullivan PF, O’Donovan MC, Scherer SW. Neale BM, Sebat J, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, 2017. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M. Mucke L, 2001. β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc. Natl. Acad. Sei. U. S. A. 98, 12245–12250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. McCarthy SE. Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D. Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee Y-H, Vacic V, Gary S, Jakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J. Goodell M, Willour VL. Derosse P, Steele j., Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR, Wellcome Trust Case Control Consortium, Craddock N, Owen MJ. O’Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PP, Deutsch CK. Rapoport J, Levy DL, King M-C, Sebat J, 2009. Microduplications of 16pll.2 are associated with schizophrenia. NaL Genet. 41, 1223–1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor J-P, Weintraub D, Aarsland D, Galvin J, Attems J, Ballard CG, Bayston A, Beach TG, Blanc F, Bohnen N, Bonanni L, Bras J, Brundin P, Burn D, Chen-Plotkin A, Duda JE, El-Agnaf O, Feldman H, Ferman TJ. Ffytche D, Fujishiro H, Galasko D, Goldman JG, Gomperts SN. Graff-Radford NR, Honig LS, Iranzo A, Kantarci K, Kaufer D, Kukull W, Lee VMY, Leverenz JB, Lewis S, Lippa C, Lunde A, Masellis M, Masliah E, McLean P, Mollenhauer B, Montine TJ, Moreno E, Mori E, Murray M, O’Brien JT, Orimo S, Postuma RB, Ramaswamy S, Ross OA, Salmon DP, Singleton A, Taylor A, Thomas A, Tiraboschi P, Toledo JB, Trojanowski JQ, Tsuang D. Walker Z, Yamada M. Kosaka K. 2017. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89, 88–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J. Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Käufer D, Kenny RA, Korczyn A, Kosaka K, Lee VMY, Lees A, Litvan L, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Consortium on DLB, 2005. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65, 1863–1872. [DOI] [PubMed] [Google Scholar]
  51. Meeus B, Verstraeten A, Crosiers D, Engelborghs S, Van den Broeck M, Mattheijssens M, Peeters K, Corsmit E, Elinck E, Pickut B, Vandenberghe R, Cras P, De Deyn PP. Van Broeckhoven C, Theuns J, 2012. DLB and PDD: a role for mutations in dementia and Parkinson disease genes? Neurobiol. Aging 33 629.e5–629.el8. [DOI] [PubMed] [Google Scholar]
  52. Mok KY, Sheerin U , Simón-Sánchez J, Salaka A, Chester L, Escott-Price V, Mantripragada K, Doherty KM, Noyce AJ, Mencacci NE, Lubbe SJ, International Parkinson’s Disease Genomics Consortium (IPDGC), Williams-Gray CH, Barker RA, van Dijk KD, Berendse HW, Heutink P, Corvol J-C, Cormier F, Lesage S, Brice A, Brockmann K, Schulte C, Gasser T, Foltynie T, Limousin P, Morrison KE, Clarke CE, Sawcer S, Warner TT, Lees AJ, Morris HR, Nalls MA, Singleton AB, Hardy J, Abramov AY, Plagnol V, Williams NM, Wood NW, 2016. Deletions at 22qll.2 in idiopathic Parkinson’s disease: a combined analysis of genome-wide association data. Lancet Neurol. 15, 585–596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, Morris CM, Theuns J, Crosiers D. Cras P, Engelborghs S, De Deyn PP, Van Broeckhoven C. Mann DMA, Snowden J, Pickering-Brown S, Halliwell N, Davidson Y, Gibbons L, Harris J„ Sheerin U-M, Bras J, Hardy J, Clark L, Marder K, Honig LS, Berg D, Maetzler W, Brockmann K, Gasser T, Novellino F, Quattrone A, Annesi G, De Marco EV, Rogaeva E, Masellis M, Black SE, Bilbao JM, Foroud T, Ghetti B, Nichols WC, Pankratz N, Halliday G, Lesage S, Klebe S, Dürr A, Duyckaerts C, Brice A, Giasson BI, Trojanowski JQ, Hurtig HI, Tayebi N, Landazabal C, Knight MA, Keller M, Singleton AB, Wolfsberg TG, Sidransky E. 2013. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol. 70, 727–735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL, Shianna KV, Yoon W, Kasperaviciute D, Gennarelli M, Strittmatter WJ, Bonvicini C , Rossi G, Jayathilake K, Cola PA, McEvoy JP, Keefe RSE, Fisher EMC, St Jean PL, Giegling I, Hartmann AM. Möller H-J, Ruppert A. Fraser G, Crombie C, Middleton LT. St Clair D, Roses AD. Muglia P, Francks C, Rujescu D. Meitzer HY. Goldstein DB, 2009. A genome-wide investigation of SNPs and CNVs in schizophrenia. Plos Genet. 5, el000373, [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, Imai H, Kitami T, Sato K, Kuroda R, Tomiyama H, Mizoguchi K, Murata M, Toda T, Imoto I, Inazawa J, Mizuno Y, Hattori N, 2006. Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson’s disease. Ann. Neurol. 59, 298–309. [DOI] [PubMed] [Google Scholar]
  56. Obi T, Nishioka K. Ross OA, Terada T, Yamazaki K, Sugiura A, Takanashi M, Mizoguchi K. Mori H, Mizuno Y, Hattori N, 2008. Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology 70, 238–241. [DOI] [PubMed] [Google Scholar]
  57. Ohtake H, Limprasert P, Fan Y, Onodera O, Kakita A, Takahashi H, Bonner LT., Tsuang DW, Murray IVJ, Lee VM-Y, Trojanowski JQ, Ishikawa A, Idezuka j., Murata M, Toda T, Bird TD. Leverenz JB, Tsuji S, La Spada AR, 2004. Beta-synuclein gene alterations in dementia with Lewy bodies. Neurology 63, 805–811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Pankratz N, Dumitriu A, Hetrick KN, Sun M, Latourelle JC, Wilk JB, Halter C, Doheny KF, Gusella JF, Nichols WC, Myers RH, Foroud T. DeStefano AL, PSG-PROGEN1 and GenePD Investigators, Coordinators and Molecular Genetic Laboratories. 2011. Copy number variation in familial Parkinson disease. PLoS One 6 e20988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Perrone F, Nguyen HP. Van Mossevelde S. Moisse M, Sieben A. Santens P, De Bleecker J, Vandenbulcke M, Engelborghs S, Baets J, Cras P, Vandenberghe R, De Jonghe P. De Deyn PP, Martin J-J. Van Damme P, Van Broeckhoven C, van der Zee J, Belgian Neurology consortium, 2017. Investigating the role of ALS genes CHCHD10 and TUBA4A in Belgian FTD-ALS spectrum patients. Neurobiol. Aging 51,177.e9–177.el6. [DOI] [PubMed] [Google Scholar]
  60. Peuralinna T, Myllykangas L, Oinas M, Nalls MA, Keage HAD, lsoviita V-M, Valori M. Polvikoski T, Paetau A, Sulkava R. lnce PG, Zaccai J, Brayne C, Traynor BJ. Hardy J, Singleton AB, Tienari PJ, 2015. Genome-wide association study of neocortical Lewy-related pathology. Ann. Clin. Transl Neurol. 2, 920–931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Rovelet-Lecrux A, Hannequin D, Guillin O, Legallic S, Jurici S, Wallon D, Frebourg T, Campion D. 2010. Frontotemporal dementia phenotype associated with MAPI gene duplication. J. Alzheimers. Dis. 21, 897–902. [DOI] [PubMed] [Google Scholar]
  62. Rovelet-Lecrux A, Lecourtois M. Thomas-Anterion C, Le Ber L, Brice A, Frebourg T, Hannequin D, Campion D. 2009. Partial deletion of the MAPT gene: a novel mechanism of FTDP-17. Hum. Mutat. 30 E591–E602. [DOI] [PubMed] [Google Scholar]
  63. Saitoh T, Xia Y, Chen X, Masliah E, Galasko D, Shults C, Thal LJ, Hansen LA., Katzman R, 1995. The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimer’s disease. Ann. Neurol. 37,110–112. [DOI] [PubMed] [Google Scholar]
  64. Santpere G, Garcia-Esparcia P, Andres-Benito P, Lorente-Galdos B, Navarro A, Ferrer I, 2018. Transcriptional network analysis in frontal cortex in Lewy body diseases with focus on dementia with Lewy bodies. Brain Pathol. 28, 315–333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Simon-Sanchez J, Scholz S, Fung HC, Matarin M, Hernandez D, Gibbs JR, Britton A, de Vrieze FW, Peckham E, Gwinn-Hardy K, Crawley A. Keen JC, Nash J, Borgaonkar D, Hardy J, Singleton A, 2007. Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals. Hum. Mol. Genet. 16,1–14. [DOI] [PubMed] [Google Scholar]
  66. Skoglund L, Ingvast S, Matsui T, Freeman SH, Frosch MP, Brundin R, Giedraitis V, Growdon JH, Hyman BT, Lannfelt L, lngelsson M, Glaser A, 2009. No evidence of PGRN or MAPT gene dosage alterations in a collection of patients with frontotemporal lobar degeneration. Dement. Geriatr. Cogn. Disord. 28, 471–475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Sleegers K, Brouwers N, Gijselinck L, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn CM, Van Broeckhoven C, 2006. APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129, 2977–2983. [DOI] [PubMed] [Google Scholar]
  68. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M, 1997. Alpha-synudein in lewy bodies. Nature 388, 839–840. [DOI] [PubMed] [Google Scholar]
  69. Stefansson H, Rujescu D, Cichon S, Pietiläinen OPH, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM. Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller H-J, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Rugged M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW. Wang AG, Ullum H. Djurovic S. Melle L, Olesen J, Kiemeney LA. Franke B. GROUP, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K, 2008. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Swaminathan S, Kim S. Shen L. Risacher SL, Foroud T, Pankratz N, Potkin SG, Huentelman MJ, Craig DW, Weiner MW, Saykin AJ, The Alzheimer’s Disease Neuroimaging Initiative Adni, 2011. Genomic copy number analysis in Alzheimer’s disease and Mild Cognitive Impairment: an ADNI study. Int. J. Alzheimers. Dis. 2011 729478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Swaminathan S, Shen L, Kim S, lnlow M, West JD, Faber KM, Foroud T, Mayeux R, Saykin AJ. Alzheimer’s Disease Neuroimaging Initiative, NIA-LOAD/NCRAD Family Study Group, 2012. Analysis of copy number variation in Alzheimer’s disease: the NIALOAD/NCRAD Family Study. Curr. Alzheimer Res. 9,801–814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Wang K, Li M, Hadley D, Liu R. Glessner J, Grant SFA, Hakonarson H, Bucan M. 2007. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 17,1665–1674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Waters CH., Miller CA, 1994. Autosomal dominant Lewy body parkinsonism in a four-generation family. Ann. Neurol. 35 59–64. [DOI] [PubMed] [Google Scholar]
  74. Webb JL, Ravikumar B, Atkins J. Skepper JN, Rubinsztein DC, 2003. Alpha-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013. [DOI] [PubMed] [Google Scholar]
  75. Weiss LA., Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MAR, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A. Tanzi RE, Stefansson K. Santangelo SL, Gusella JF, Sklar P, Wu B-L, Daly MJ, Autism Consortium, 2008. Association between microdeletion and microduplication at 16pll.2 and autism. N. Engl. J. Med. 358, 667–675. [DOI] [PubMed] [Google Scholar]
  76. Zhang M, Xi Z, Zinman L, Bruni AC, Maletta RG, Curcio SAM, Rainero I, Rubino E, Pinessi L, Nacmias B, Sorbi S, Galimberti D, Lang AE, Fox S, Surace EI, Ghani M, Guo J, Sato C, Moreno D, Liang Y, Keith J, Traynor BJ, St George-Hyslop P, Rogaeva E, 2015. Mutation analysis of CHCHD10 in different neurodegenerative diseases. Brain 138, e380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Zheng X, Demirci FY, Barmada MM, Richardson GA, Lopez OL, Sweet RA, Kamboh ML, Feingold E, 2015. Genome-wide copy-number variation study of psychosis in Alzheimer’s disease. Transl. Psychiatry 5, e574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Zheng X, Demirci FY, Barmada MM, Richardson GA. Lopez OL, Sweet RA, Kamboh ML, Feingold E, 2014. A rare duplication on chromosome 16pll.2 is identified in patients with psychosis in Alzheimer’s disease. PLoS One 9, e111462. [DOI] [PMC free article] [PubMed] [Google Scholar]

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