Table 3.
Top 30 single SNPs located in gene regions (including 100 kb of flanking sequences) ranked according to the mean rank calculated across three statistics as reported by Lesch et al. (2008) for association with persistent ADHD in adults
| SNP | Mean of ranks | ANOVA P value | Locus | Physical position | Position | Gene functiona | Additional remarks |
|---|---|---|---|---|---|---|---|
| rs11243897 | 1 | 5.63E-08 | 9q34.13 | 134608104 | In intron of C9orf98 | Encodes chromosome 9 open reading frame 98, a putative adenylate kinase-like protein of unknown function expressed in brain and other tissues | |
| rs2587695 | 2 | 2.73E-07 | 2q14.2 | 120038287 | In intron of PCDP1 = MGC33657 | Encodes primary ciliary dyskinesia protein 1, a protein playing an important role in ciliary and flagellar biogenesis and motility of (among others) the cilia of respiratory epithelial cells and brain ependymal cells in both mice and humans. Finding lies within linkage region for schizophrenia from meta-analysis (Lewis et al. 2003) | |
| rs864643 | 4 | 1.30E-08 | 3p22.2 | 39530584 | In 3′UTR/intron of MOBP | Encodes myelin-associated oligodendrocyte basic protein. The gene shows altered expression in several areas of the brain of patients with substance use disorders (Albertson et al. 2004; Mitkus et al. 2008). Finding lies close to a linkage region for schizophrenia from meta-analysis (Lewis et al. 2003) | Also lies within suggestive linkage region for ADHD reported in the same publication (Lesch et al. 2008) |
| rs2199161 | 11 | 1.62E-06 | 5q13.2 | 71446112 | In intron of MAP1B | Encodes microtubule-associated protein 1B, a member of a protein family thought to be involved in microtubule assembly, which is an essential step in neurogenesis. Gene knockout studies of the mouse microtubule-associated protein 1B gene suggested an important role in development and function of the nervous system. Finding lies within linkage region for ADHD from meta-analysis (Zhou et al. 2008c) | Also lies within suggestive linkage region for ADHD reported in the same publication (Lesch et al. 2008) |
| rs16928529 | 12 | 3.90E-06 | 10q22.1 | 72652991 | In intron of UNC5B | Encodes unc-5 homolog B (C. elegans), which belongs to a family of netrin-1 receptors thought to mediate the chemorepulsive effect of netrin-1 on specific axons. Finding lies in linkage region for bipolar disorder (1997) | |
| rs2677744 | 13 | 9.69E-07 | 15q26.1 | 89251445 | In intron of MAN2A2 | Encodes mannosidase, alpha, class 2A, member 2, expressed in brain and many other tissues. The protein is involved in N-glycan synthesis. The finding lies close to linkage regions for autism (Szatmari et al. 2007b) and major depressive disorder (Holmans et al. 2007) | |
| rs7175404 | 14 | 6.03E-07 | 15q26.1 | 91837692 | In intron of AK094352 | Gene of unknown function. The finding lies close to linkage region for major depressive disorder (Holmans et al. 2007) | |
| rs10983238 | 15 | 1.37E-07 | 9q33.1 | 118373504 | In intron of ASTN2 | Encodes astrotactin 2, a membrane protein expressed in multiple tissues including brain. It is critically involved in neuron-glia binding during the developmental periods of glial-guided cell migration and assembly into neuronal layers in the developing brain (Lesch et al. 2008). A homologue of the gene, ASTN, is involved in neuronal migration (Vrijenhoek et al. 2008).The gene was found disrupted by rare CNVs in schizophrenia patients (Vrijenhoek et al. 2008) and patients with autism (Marshall et al. 2008) shows association in GWAS of multiple addiction-related traits (Uhl et al. 2008a), as well as of schizophrenia (Sullivan et al. 2008) | Also lies within suggestive linkage region for ADHD reported in the same publication (Lesch et al. 2008). Association also observed in the 50 K GWAS in the same publication. Three SNPs in the gene are among the highest-ranking 260 in the analysis |
| rs2281597 | 18 | 5.41E-07 | 1p35.1 | 34132445 | In intron of CSMD2 | Encodes CUB and Sushi multiple domains 2, a protein with a potential role in cell adhesion and neurogenesis. Intermediate expression in fetal brain, adult brain, spinal cord, and all specific adult brain regions examined. Lower levels were detected in spleen, lung, and testis, and little to no expression was detected in the other tissues examined. The protein product is enriched in axonal growth cones and is involved in neuronal outgrowth during formation of neuronal circuits (Lesch et al. 2008). CSMD2 and its homologue CSMD1 have been found associated with addiction-related phenotypes in multiple GWAS (Uhl et al. 2008a) | |
| rs2502731 | 19 | 1.58E-06 | 9q34.11 | 130016378 | In intron of DNM1 | Encodes dynamin 1, a GTPase involved in clathrin-mediated endocytosis and other vesicular trafficking processes, especially during high levels of neuronal activity. The finding lies close to linkage regions for autism (Szatmari et al. 2007 b). | |
| rs412050 | 23 | 5.83E-06 | 22q11.22 | 20637519 | Immediately downstream of PPM1F | The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. Calcium/calmodulin-dependent protein kinase II gamma (CAMK2G/CAMK-II) is found to be one of the substrates of this phosphatase. Expressed in brain and other tissues. Finding lies in linkage region for schizophrenia from meta-analysis (Lewis et al. 2003) and close to linkage finding for smoking (Saccone et al. 2007) | Site known for CNVs |
| rs515910 | 24 | 4.36E-06 | 10q25.1 | 105956394 | In intron of C10orf79 | Gene/protein of unknown function expressed in brain and other tissues | |
| rs220470 | 28 | 1.34E-07 | 17p13.2 | 3611724 | ITGAE | Encodes integrin alpha E. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Expressed in multiple tissues including brain. Finding lies within linkage region for ADHD from meta-analysis (Zhou et al. 2008c) | Also lies within suggestive linkage region for ADHD reported in the same publication (Lesch et al. 2008). Another integrin alpha, encoded by ITGA11, also is listed at rank 50 |
| rs4964805 | 32 | 4.74E-06 | 12q23.3 | 102716954 | In intron of NT5DC3 | Encodes 5′-nucleotidase domain containing 3, a potential oncogene. Expression is found in brain and several other tissues. Finding lies close to linkage regions for the personality trait neuroticism (Fullerton et al. 2003) and a neuropsychological ADHD endophenotype (Rommelse et al. 2008c) | 19 additional SNPs in the gene showed association with ADHD |
| rs2242073 | 40 | 8.27E-06 | 2q33.3 | 208702290 | In intron of CRYGC | Encodes crystallin gamma C. Crystallins constitute the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. No reports of expression in brain | Site known for CNVs (Kidd et al. 2008) |
| rs1555322 | 49 | 3.60E-06 | 20q11.22 | 33312595 | In intron of MMP24 | Encodes matrix metallopeptidase 24 (membrane-inserted). Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling. Expression is found in brain and several other tissues. Finding lies in likage region for autism (Allen-Brady et al. 2008) | |
| rs7164335 | 50 | 1.30E-07 | 15q23 | 66502086 | ITGA11 | Encodes integrin alpha 11. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Expressed in multiple tissues including brain. The finding lies close to linkage regions for autism (Szatmari et al. 2007b) |
Site known for CNVs. Another integrin-encoding gene ITGAE, also is listed under rank 28 |
| rs11594082 | 52 | 1.00E-05 | 10q22.1 | 72969259 | In intron of CDH23 | Encodes cadherin-like 23, a member of the cadherin superfamily, whose genes encode calcium dependent cell–cell adhesion glycoproteins. Expressed in the neurosensory epithelium, the protein is thought to be involved in stereocilia organization and hair bundle formation; also expressed in brain. The gene is involved in deafness. Finding lies close to linkage region for bipolar disorder (1997). Gene shows association with schizophrenia at P values of 10−4 (Sullivan et al. 2008) | |
| rs7995215 | 53 | 1.35E-08 | 13q31.3 | 93206507 | In intron of GPC6 | Encodes glypican 6. The glypicans comprise a family of glycosylphosphatidylinositol-anchored heparan sulfate proteoglycans. The glypicans have been implicated in the control of cell growth and division. Glypican 6 is a putative cell surface coreceptor for growth factors, extracellular matrix proteins, proteases and anti-proteases. Expressed in multiple tissues including brain. SNPs in the close vicinity of this finding showed association at 10−4 in GWAS for bipolar disorder (Sklar et al. 2008). Gene shows association with schizophrenia (Sullivan et al. 2008) and bipolar disorder (Sklar et al. 2008) at P = 10−4 and CNVs in the gene have been noted in a study on autism (Marshall et al. 2008) | |
| rs2241685 | 54 | 8.11E-06 | 2p25.3 | 1905000 | In intron of MYT1L | Encodes myelin transcription factor 1-like, a protein of unknown function, which shows expression in brain and other organs. The gene was found disrupted by rare CNVs in schizophrenia patients (Vrijenhoek et al. 2008) | |
| rs469727 | 55 | 7.54E-06 | 5q22.2 | 112270867 | In intron of REEP5 | Encodes the receptor accessory protein 5, expressed in many tissues including brain. The protein may be involved in the transport of G-protein-coupled receptors to the cell membrane | Also lies within suggestive linkage region for ADHD reported in the same publication (Lesch et al. 2008). Association also observed in the 50 K GWAS in the same publication |
| rs13395022 | 57 | 9.68E-06 | 2p12 | 79735768 | In intron of CTNNA2 | Encodes catenin alpha 2, expressed in brain and other tissues. The activity of cadherins, which mediate homophilic cell–cell Ca(2+)-dependent association, depends on their anchorage to cytoskeleton via catenins. Catenin alpha 2 functions as a critical agent to regulate the stability of synaptic contacts. Cell-adhesion complexes of catenin alpha 2 with cadherin are likely most important in cerebellar and hippocampal lamination. Finding lies within a linkage region for schizophrenia from meta-analysis (Lewis et al. 2003). Gene shows association with schizophrenia (Sullivan et al. 2008) at p-values of 10−5 and bipolar disorder (Wellcome Trust Case Control Consortium 2007) at 10−4 | Gene also shows association with ADHD at 10−4 in GWAS of Neale et al. (2008a) |
| rs10786284 | 61 | 1.96E-06 | 10q24.1 | 98125495 | In intron of TLL2 | Encodes tolloid-like 2, an astacin-like zinc-dependent metalloprotease and is a subfamily member of the metzincin family. Its function is not clear, but it shows expression in brain | The homologue TLL1 shows association with ADHD and related quantitative traits in the GWAS of Neale et al. (2008a) and Lasky-Su et al. (2008b) |
| rs12453316 | 62 | 1.72E-05 | 17q25.1 | 69027654 | Within 83 kb of SDK2 | Encodes sidekick homologue 2, a member of the immunoglobulin superfamily. Chicken Sdk2 mediates homophilic adhesion and direct laminar targeting of neurites | |
| rs2237349 | 64 | 4.63E-06 | 7p15.1 | 28729488 | CREB5 | Encodes cAMP-responsive element binding protein 5, which belongs to the cAMP response element (CRE)-binding protein family. Members of this family contain zinc-finger and bZIP DNA-binding domains. The encoded protein specifically binds to CRE as a homodimer or a heterodimer with c-Jun or CRE-BP1, and functions as a CRE-dependent trans-activator. Expressed in brain, especially fetal brain and prefrontal cortex, and other tissues. Finding is close to linkage region for neuroticism (Fullerton et al. 2003), and in a region associated with bipolar disorder in a GWAS at 10−4 (Wellcome Trust Case Control Consortium 2007). Gene shows association with schizophrenia in GWAS (Sullivan et al. 2008) at P = 10−4 | |
| rs10514604 | 69 | 8.06E-07 | 16q24.1 | 83003885 | ATP2C2 | Encodes Ca2+ transporting ATPase type 2C member 2, potentially involved in cellular detoxification of Mn2+ ions (Xiang et al. 2005). Shows expression predominantly in brain and testis. Finding falls into the significant linkage region for ADHD as observed in meta-analysis (Zhou et al. 2008c) | Also lies within suggestive linkage region for ADHD reported in the same publication (Lesch et al. 2008). Association also observed in the 50 K GWAS in the same publication |
| rs2842643 | 70 | 3.28E-06 | 6p21.1 | 41758714 | Immediately upstream of TFEB | Encodes transcription factor EB of unknown function. The gene is expressed in brain and many other tissues. The finding lies within/close to regions of suggestive linkage to ADHD (Zhou et al. 2008c) and schizophrenia (Lewis et al. 2003) from meta-analyses | Site known for CNVs |
| rs3893215 | 73 | 2.56E-05 | 11p15.1 | 17721406 | In intron of KCNC1 | Encodes potassium voltage-gated channel Shaw-related subfamily member 1, a protein belonging to the delayed rectifier class of channel proteins and an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. The finding is present close to/within regions of (suggestive) linkage to autism from meta-analysis (Trikalinos et al. 2006) and primary studies (Duvall et al. 2007; Szatmari et al. 2007b) | |
| rs11646411 | 79 | 7.40E-06 | 16q23.3 | 81304438 | In intron of CDH13 | Encodes cadherin 13, a member of the cadherin superfamily. The encoded protein is a calcium- dependent cell–cell adhesion glycoprotein. This particular cadherin is a putative mediator of cell–cell interaction in the heart and may act as a negative regulator of neural cell growth. Lies within the only significant linkage region for ADHD as determined in met-analysis (Zhou et al. 2008c). Has earlier shown association with metamphetamine dependence in GWAS (Uhl et al. 2008b) as well as multiple other addiction related phenotypes (Uhl et al. 2008a) | Most significant finding in quantitative GWAS by Lasky-Su et al. (2008b), and shows association in the GWAS in adult ADHD by Lesch et al. (2008) |
| rs3799977 | 80 | 4.90E-06 | 6p21.1 | 44945334 | In intron of SUPT3H | Encodes suppressor of Ty 3 homolog, expressed in brain and other tissues, with a potential role in transcription. The finding lies within/close to regions of suggestive linkage to ADHD (Zhou et al. 2008c) and schizophrenia (Lewis et al. 2003) from meta-analyses |
aWhere not indicated otherwise, the information is derived from the UCSC Browser, NCBI’s OMIM, Gene and Unigene databases, and the Sullivan Lab Evidence Project website (location of SNP expanded by ±5 Mb for genome-wide linkage scans, ±5 kb for GWAS, microarray and CNV studies, and ±50 kb for signposts)