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. Author manuscript; available in PMC: 2019 Aug 1.
Published in final edited form as: Gene. 2016 Apr 7;586(1):136–147. doi: 10.1016/j.gene.2016.04.011

High-resolution chromosome ideogram representation of recognized genes for bipolar disorder

Lindsay N Douglas 1,1, Austen B McGuire 1,1, Ann M Manzardo 1, Merlin G Butler 1,*
PMCID: PMC6675571  NIHMSID: NIHMS1043185  PMID: 27063557

Abstract

Bipolar disorder (BPD) is genetically heterogeneous with a growing list of BPD associated genes reported in recent years resulting from increased genetic testing using advanced genetic technology, expanded genomic databases, and better awareness of the disorder. We compiled a master list of recognized susceptibility and genes associated with BPD identified from peer-reviewed medical literature sources using PubMed and by searching online databases, such as OMIM. Searched keywords were related to bipolar disorder and genetics. Our compiled list consisted of 290 genes with gene names arranged in alphabetical order in tabular form with source documents and their chromosome location and gene symbols plotted on high-resolution human chromosome ideograms. The identified genes impacted a broad range of biological pathways and processes including cellular signaling pathways particularly cAMP and calcium (e.g., CACNA1C, CAMK2A, CAMK2D, ADCY1, ADCY2); glutamatergic (e.g., GRIK1, GRM3, GRM7), dopaminergic (e.g., DRD2, DRD4, COMT, MAOA) and serotonergic (e.g., HTR1A, HTR2A, HTR3B) neurotransmission; molecular transporters (e.g., SLC39A3, SLC6A3, SLC8A1); and neuronal growth (e.g., BDNF, IGFBP1, NRG1, NRG3). The increasing prevalence of BPD calls for better understanding of the genetic etiology of this disorder and associations between the observed BPD phenotype and genes. Visual representation of genes for bipolar disorder becomes a tool enabling clinical and laboratory geneticists, genetic counselors, and other health care providers and researchers easy access to the location and distribution of currently recognized BPD associated genes. Our study may also help inform diagnosis and advance treatment developments for those affected with this disorder and improve genetic counseling for families.

Keywords: Bipolar disorder, Chromosome ideograms, Major affective disorder, Manic-depressive illness, Susceptibility genes

1. Introduction

Bipolar disorder (BPD) or major affective disorder is largely undiagnosed but known to cause unusual shifts in behavior, including mood, activity levels, and ability to perform everyday tasks. According to the Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5), BPD can be separated into four basic types: Bipolar I Disorder (BP-I), Bipolar II Disorder (BP-II), Bipolar Disorder Not Otherwise Specified (BP-NOS), and Cyclothymic Disorder. The diagnosis is dependent on severity and length of the manic and depressive phases [Hirschfeld et al., 2000, 2003a, 2003b; Juvenile Bipolar Research Foundation (http://www.jbrf.org/diagnosis-by-the-dsm/); National Institute of Mental Health (http://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml#part_145403)]. The twelve month prevalence of BPD is 1.5% for the adult population in the U.S., 0.4% for BP-I, 0.3% for BP-II, and 0.8% for BP-NOS. The lifetime prevalence of BPD in the U.S. population is 2.4% for the total population; 0.6% for BP-I, 0.4% for BP-II, and 1.4% for BP-NOS (Merikangas et al., 2011). Men and women are equally affected by BPD, but women are three times more likely than men to experience the rapid cycling process and tend to experience the depressive and mixed episodes more often than men (Merikangas et al., 2011). Most individuals are diagnosed with bipolar disorder around the age of 25 years, but some individuals are diagnosed as young as six years of age or as late as 40 and 50 years [Birmaher et al., 2006; Geller et al., 2004; Depression and Bipolar Support AllianceDepression and Bipolar Support Alliance (http://www.dbsalliance.org/site/PageServer?pagename=education_statistics_bipolar_disorder)]. Given the nature of the disorder, it is common for individuals with BPD to be misdiagnosed as having another mental illness, which can hinder recognition and treatment [Depression and Bipolar Support Alliance (http://www.dbsalliance.org/site/PageServer?pagename=education_statistics_bipolar_disorder)]. BPD often coexists with other Axis I and Axis II disorders [e.g. substance abuse, anxiety disorders (such as agoraphobia, post-traumatic stress disorder, and social phobia), and eating disorders] with reported rates of lifetime psychiatric comorbidity in bipolar I samples ranging from 50% to 70% (McElroy et al., 2001). Approximately 20% of the children and adolescents experiencing major depression will develop bipolar disorder within five years of being diagnosed with depression (Birmaher et al., 2006; McClellan et al., 2007). Almost one-third of adolescents with depression are actually experiencing early onset of bipolar disorder.

Numerous twin and family studies have supported a genetic contribution to the risk of developing BPD. Monozygotic twins show greater concordance with psychopathology than dizygotic twins and individuals with affected relatives show an increased chance of developing bipolar and/or unipolar depression (Smoller and Finn, 2003). One affected parent is associated with a 15 to 25% elevation in risk of BPD while two affected parents shows a 50 to 75% increase [Smoller and Finn, 2003; Depression and Bipolar Support Alliance (http://www.dbsalliance.org/site/PageServer?pagename=education_statistics_bipolar_disorder)]. Never-the-less, bipolar disorder is a complex genetic disorder that does not follow Mendelian inheritance patterns with no identifiable “gene of major effect” found for the majority of BPD cases. There are also several chromosomal regions, susceptibility loci and implicated genes for BPD that have been repeatedly reported as associated with the disorder through linkage, candidate and genome-wide association studies (Craddock and Jones, 1999; Craddock et al., 2005). Interactions between numerous genes in multiple overlapping pathways and functions reduce the likelihood of one-to-one correspondence for any single “causal” bipolar disorder gene mutation (Potash and DePaulo, 2000).

Over the last few decades, researchers have identified numerous candidate genes associated with BPD using various methodologies, including genotyping single-nucleotide polymorphisms (SNPs), identifying cytogenetic abnormalities (i.e., chromosomal breakpoints which lead to the loss or alteration of specific genes), or convergent functional genomics (Cichon et al., 2009). We used existing literature and genomic databases to obtain evidence to compile a master list of currently recognized genes with their locations plotted on high-resolution chromosome ideograms (850 band level) associated with BPD. In tabular form, we listed the individual gene symbol, expanded name, and chromosome location alongside the reference source providing the information.

2. Material and methods

We used computer-based internet websites and PubMed (https://www.ncbi.nlm.nih.gov/pubmed) to search for key words based on the genetics of bipolar disorder. Articles were obtained by searching PubMed and Online Mendelian Inheritance in Man (OMIM: http://www.ncbi.nlm.nih.gov/omim) databases with the following search words: bipolar disorder (BPD), bipolar, major affective disorder, bipolar affective disorder (BPAD), bipolar syndrome, and manic depressive psychosis. We examined literature found in medical journals after our search for genetic involvement for BPD. Some articles we found had their own compilation of susceptibility genes for BPD with references to their own sources which we then further studied (Thomson et al., 2005; Le-Niculescu et al., 2009; Cichon et al., 2009; Shinozaki and Potash, 2014). The articles were then prioritized based on the following considerations: sample size, use of standardized diagnostic criteria, types of genetic testing such as genome wide association studies and validated methods (e.g., convergent functional genomics, genotyping SNPs or identifying cytogenetic abnormalities), and quality with reliability of the genetic data and presentation. GeneCards (http://www.genecards.org/) was the primary source for determining the location of the gene or gene locus. The cytogenetic location of the gene was provided by Ensembl, Entrez Gene, or the Human Genome Organization Gene Nomenclature Committee (HGNC).

BPD is a heterogeneous disorder involving many genes acting individually or in combination and responsive to environmental stimuli. We compiled a list of genes from the major sources and their references for a total of 290 genes. Our paper focused on genes associated with BPD by at least one mechanism of proven association with or susceptibility to BPD. Research articles were not limited to causal relationships to BPD. For example, Le-Niculescu and others used convergence of microsatellite markers for which at least one published study showed evidence for linkage for BPD, or a positive association study for the gene itself reported in previous literature (Le-Niculescu et al., 2009). Many of the genes on our list were found in multiple research studies and were reported more than once for being associated with BPD. Some studies considered target neurochemical pathways rather than susceptibility loci. These genes were included on our list if they were also recognized by a peer-reviewed publication (e.g., PubMed) with supporting evidence (e.g., GWAS, informative SNPs, genetic linkage, or identified gene mutations) as a BPD associated gene (Le-Niculescu et al., 2009; Cichon et al., 2011). Other supporting genetic evidence can be found in the National Center for Biotechnology Resources at https://www.ncbi.nlm.nih.gov/gene.

3. Results

By using online databases and existing literature in peer-reviewed journals, we were able to compile a master list of 290 recognized genes associated with BPD. These genes were clinically relevant, or related to susceptibility of BPD. The position for each of the recognized or susceptibility genes for BPD were plotted on the high-resolution chromosome ideograms (850 band level), as shown in Fig. 1. We have also included gene symbols, expanded names, chromosome band location and reference sources in Table 1 for the 290 genes recognized as playing a role in BPD. The distribution of BPD genes is shown in Table 2 among individual chromosomes and chromosome arms arranged by the size for each chromosome (largest chromosome represented by the smallest number) in relationship to the proportion of total genes for BPD.

Fig. 1.

Fig. 1.

Fig. 1.

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High-resolution chromosome ideograms (850 band level) with the BPD gene symbol placed at the chromosomal band location. The centromere area, highlighted in black, separates the upper short “p” arm and the lower long “q” arm for each chromosome. The gene symbols are arranged in alphabetical order with the expanded name and chromosome band position listed in Table 1.

Table 1.

Known and candidate genes for bipolar disorder (BPD) and overlap with schizophrenia and autism.

Gene symbol Gene name Location Source
ABCA13* ATP-binding cassette, subfamily A, member 13 7p12.3F Knightet al. (2009)
ABCCI2 ATP-binding cassette, subfamily C, member 12 16q12.1 Xu et al. (2014)
ABHD2 Abhydrolase domain containing 2 15q26.1 Xu et al. (2014)
ACACB Acetyl-coenzyme A carboxylase beta 12q24.11 Le-Niculescu et al. (2009)
ACE* Angiotensin I converting enzyme 17q23.3 Zou et al. (2011)
ACOXL Acyl-CoA oxidase-like 2q13 Xu et al. (2014)
ADCY1* Adenylate cyclase 1 (brain) 7p12.3 Le-Niculescu et al. (2009)
ADCY2 Adenylate cyclase 2 5p15.31 Mühleisen et al. (2014)
ADCYAP1* Adenylate cyclase activating polypeptide 1 (pituitary) 18p11.32 Le-Niculescu et al. (2009)
AFF1 AF4/FMR2 family, member 1 4q21.3 Xu et al. (2014)
AGO2 Argonate RISC catalytic component 2 8q24.3 Le-Niculescu et al. (2009)
AK3 Adenylate kinase 3 9p24.1 Le-Niculescu et al. (2009)
ALDHIAI Aldehyde dehydrogenase 1 family, member A1 9q21.13 Le-Niculescu et al. (2009)
ALG9 ALG9, alpha-1,2-mannosyltransferase 11q23.1 Baysal et al. (2002)
ALKBH8 AlkB, alkylation repair homolog 8 (Escherichia coli) 11q22.3 Xu et al. (2014)
ANK2# Ankyrin 2, neuronal 4q25 Le-Niculescu et al. (2009)
ANK3*# Ankyrin 3 10q21.2 Takata et al. (2011)
APP# Amyloid beta (A4) precursor protein 21q21.3 Le-Niculescu et al. (2009)
ARHGAP15# Rho GTPase activating protein 15 2q22.2 Xu et al. (2014)
ARNT2# Aryl-hydrocarbon receptor nuclear translocator 2 15q25.1 Xu et al. (2014)
ARNTL* Aryl hydrocarbon receptor nuclear translocator-like 11p15.3 Le-Niculescu et al. (2009)
ASMT# Acetylserotonin O-methyltransferase Xp22.33 or Yp11.32 Etain et al. (2012)
ATP2A2 ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 12q24.11 Xu et al. (2014)
ATXN1* Ataxin 1 6p22.3 Le-Niculescu et al. (2009)
BAZ2B Bromodomain adjacent to zinc finger domain, 2B 2q24.2 Xu et al. (2014)
BCR Breakpoint cluster region 22q11.23 Hashimoto et al. (2005)
BDNF*# Brain-derived neurotrophic factor 11p14.1 Fan and Sklar (2008)
BRD1* Bromodomain containing 1/zinc finger, BED-type containing 4 22q13.33 Nyegaard et al. (2010)
BRE Brain and reproductive organ-expressed (TNFRSF1Amodulator) 2p23.2 Cichon et al. (2011)
C9ORF72 Chromosome 9 open reading frame 72 9p212 Meisler et al. (2013)
CACNA1C*# Calcium channel, voltage-dependent, L type, alpha 1C subunit 12p13.33 Ou et al. (2015)
CACNB2*# Calcium channel, voltage dependent, beta 2 subunit 10p12.33 Le-Niculescu et al. (2009)
CAMK2A Calcium/calmodulin-dependent protein kinase II, alpha 5q32 Le-Niculescu et al. (2009)
CAMK2D Calcium/calmodulin-dependent protein kinase II, delta 4q26 Le-Niculescu et al. (2009)
CAMTA1# Calmodulin binding transcription activator 1 1p36.31 Cichon et al. (2011)
CCDC132 Coiled-coil domain containing 132 7q21.3 Cichon et al. (2011)
CCDC148 Coiled-coil domain containing 148 2q24.1 Xu et al. (2014)
CD36 CD36 molecule (Thrombospondin receptor) 7q21.11 Blair et al. (2006)
CD44# CD44 molecule (Indian blood group) 11p13 Le-Niculescu et al. (2009)
CDH7 Cadherin 7, type 2 18q22.1 Soronen et al. (2010)
CDH13 Cadherin 13 16q23.3 Le-Niculescu et al. (2009)
CDHR3 Cadherin-related family member 3 7q22.3 Xu et al. (2014)
CDK14 Cyclin-dependent kinase 14 7q21.13 Le-Niculescu et al. (2009)
CELF2 CUGBP, elav-like family member 2 10p13 Le-Niculescu et al. (2009)
CELSR1 Cadherin, EGF LAG seven-pass G-type receptor 1 22q13.31 Le-Niculescu et al. (2009)
CEP128 Centrosomal protein 128 kDa 14q31.1 Le-Niculescu et al. (2009)
CFAP57 Cilia and flagella associated protein 57 1p342 Xu et al. (2014)
CGRRF1 Cell growth regulator with ring finger domain 1 14q22.2 Xu et al. (2014)
CHRNA7*# Cholinergic receptor, nicotinic, alpha 7 (neuronal) 15q13.3 Le-Niculescu et al. (2009)
CLOCK* Clock circadian regulator 4q12 Benedetti et al. (2003)
CLSTN2 Calsyntenin 2 3q23 Le-Niculescu et al. (2009)
CMIP# C-Maf inducing protein 16q23.2 Xu et al. (2014)
CNTNAP5*# Contactin associated protein-like 5 2q14.3 Baum et al. (2008a, 2008b)
COMT* Catechol-O-methyltransferase 22q11.21 Zhang et al. (2009)
CREBBP# CREB binding protein 16p13.3 Le-Niculescu et al. (2009)
CSMD1*# CUB and sushi multiple domains 1 8p23.2 Sklar et al. (2008)
DAOA* D-Amino acid oxidase activator 13q33.2 Detera-Wadleigh and McMahon (2006)
DAPK1 # Death-associated protein kinase 1 9q21.33 Le-Niculescu et al. (2009)
DCLK1 Doublecortin-like kinase 1 13q13.3 Le-Niculescu et al. (2009)
DCTN5# Dynactin 5 (P25) 16p12.2 Burton et al. (2007)
DDX27 DEAD (Asp-Glu-Ala-Asp) box polypeptide 27 20q13.13 Xu et al. (2014)
DFNB31 Deafness, autosomal recessive 31 9q32 Ollila et al. (2009)
DGKH Diacylglycerol kinase, eta 13q14.11 Baum et al. (2008a, 2008b)
DIAPH1 Diaphanous-related formin 1 5q31.3 Le-Niculescu et al. (2009)
DIP2C Disco-interacting protein 2 homolog C (Drosophila) 10p15.3 Djurovic et al. (2010)
DISC1 *# Disruption in schizophrenia 1 1q42.2 Hodgkinson et al. (2004)
DLG2* Discs, large homolog 2 (Drosophila) 11q14.1 Xu et al. (2014)
DNAJC16 DnaJ (Hsp40) homolog, subfamily C, member 16 1p36.21 Xu et al. (2014)
DNMT1 * DNA methyltransferase 1 19p13.2 Veldic et al.(2005)
DOCK3 Dedicator of cytokinesis 3 3p212 Baum et al. (2008a, 2008b)
DPP10*# Dipeptidyl-peptidase 10 (non-functional) 2q14.1 Le-Niculescu et al. (2009)
DPY19L3 Dpy-19-like 3 (Caenorhabditis elegans) 19q13.11 Smith et al. (2009)
DRD2*# Dopamine receptor D2 11q23.2 Le-Niculescu et al. (2009)
DRD4* Dopamine receptor D4 11p15.5 López León et al. (2005)
DSCAM# Down syndrome cell adhesion molecule 21q22.2 Xu et al. (2014)
DSEL Dermatan sulfate epimerase-like 18q22.1 Goossens et al. (2003)
DST# Dystonin 6p12.1 Le-Niculescu et al. (2009)
DTNBP1* Dystrobrevin binding protein 1 6p22.3 Gaysina et al. (2009)
EDAR Ectodysplasin A receptor 2q12.3 Xu et al. (2014)
EGFEM1P EGF-Like and EMI domain containing 1, pseudogene 3q26.2 Xu et al. (2014)
EGFR Epidermal growth factor receptor 7p11.2 Sklaret al.(2008)
EIF2S3# Eukaryotic translation initiation factor 2, subunit 3 gamma, 52 kDa Xp22.11 Cichon et al., (2011)
ELAVL2 ELAV like neuron-specific RNA binding protein 2 9p21.3 Le-Niculescu et al. (2009)
EPHA5 EPH receptor 5 4q13.1 Le-Niculescu et al. (2009)
FAM13A1 Family with sequence similarity 13, member A 4q22.1 Le-Niculescu et al. (2009)
FAM83F Family with sequence similarity 83, member F 22q13.1 Xu et al. (2014)
FBN1 Fibrillin 1 15q21.1 Djurovic et al. (2010)
FBXO28 F-Box protein 28 1q42.11 Xu et al. (2014)
FGF12 Fibroblast growth factor 12 3q28 Cichon et al. (2011)
FGFR2 Fibroblast growth factor receptor 2 10q26.13 Xu et al. (2014)
FGGY FGGY carbohydrate kinase domain containing 1p32.1 Kerner et al. (2013)
FRMD3 FERM domain containing 3 9q21.32 Djurovic et al. (2010)
FOXN3 Forkhead box N3 14q32.11 Baum et al. (2008a, 2008b)
FOXP1# Forkhead box P1 3p14.1 Le-Niculescu et al. (2009)
FOXP2*# Forkhead box P2 7q31.1 Xu et al. (2014)
FUT9 Fucosyltransferase 9 (alpha (1,3) fucosyltransferase) 6q16.1 Le-Niculescu et al. (2009)
GAA Glucosidase, alpha; acid 17q25.3 Le-Niculescu et al. (2009)
GABBR2 Gamma-aminobutyric acid (GABA) B receptor 2 9q22.33 Djurovic et al. (2010)
GABRB1# Gamma-aminobutyric acid (GABA) A receptor, beta 1 4p12 Burton et al. (2007)
GAD2* Glutamate decarboxylase 2 (pancreatic islets and brain, 65 kDa) 10p11.23 Heckers et al. (2002)
GNAI1 Guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1 7q21.11 Le-Niculescu et al. (2009)
GNA12 Guanine nucleotide binding protein (G protein) alpha 12 7p22.2 Le-Niculescu et al. (2009)
GNAL Guanine nucleotide binding protein (G protein), alpha activating activity polypeptide, olfactory type 18p11.21 Corradi et al. (2005)
GNG4 Guanine nucleotide binding protein (G protein), gamma 4 1q42.3 Cichon et al. (2011)
GPR50* G protein-coupled receptor 50 Xq28 Thomson et al. (2005)
GRIA1* Glutamate receptor, ionotropic, AMPA1 (alpha 1) 5q33.2 Le-Niculescu et al. (2009)
GRIK1 Glutamate receptor, ionotropic, kainate 1 21q21.3 Le-Niculescu et al. (2009)
GRIK2# Glutamate receptor, ionotropic, kainite 2 6q16.3 Shaltiel et al. (2008)
GRIK4* Glutamate receptor, ionotropic, kainite 4 11q23.3 Blackwood et al. (2007)
GRIN3A* Glutamate receptor, ionotropic, N-methyl-D-aspartate 3A 9q31.1 Cichon et al. (2011)
GRM1# Glutamate receptor, metabotropic 1 6q24.3 Le-Niculescu et al. (2009)
GRM3* Glutamate receptor, metabotropic 3 7q21.11 Le-Niculescu et al. (2009)
GRM7* Glutamate receptor, metabotropic 7 3p26.1 Burton et al. (2007)
GSK3B*# Glycogen synthase kinase 3 beta 3q13.33 Le-Niculescu et al. (2009)
GSTA2 Glutathione S-transferase alpha 2 6p12.2 Le-Niculescu et al. (2009)
GUCA1A Guanylate cyclase activator 1 A 6p21.1 Xu et al. (2014)
HMOX1 Heme oxygenase 1 22q12.3 Le-Niculescu et al. (2009)
HTR1A* 5-Hydroxytryptamine (serotonin) receptor 1A, G protein-coupled 5q12.3 Kishi et al. (2011)
HTR2A*# 5-Hydroxytryptamine (serotonin) receptor 2A, G-protein-coupled 13q14.2 Le-Niculescu et al. (2009)
HTR3B* 5-Hydroxytryptamine (serotonin) receptor 3B, ionotropic 11q23.1 Hammer et al. (2012)
HTR4* 5-Hydroxytryptamine (serotonin) receptor 4, G-protein coupled 5q32 Ohtsuki et al. (2002)
ICAM3 Intercellular adhesion molecule 3 19p13.2 Cichon et al. (2011)
IGFBP7 Insulin-like growth factor binding protein 7 4q12 Xu et al. (2014)
IGSF21 Immunoglobin superfamily, member 21 1p36.13 Cichon et al. (2011)
IMPA2* Myo-inositol monophosphatase 2 18p11.21 Sjøholt et al. (2004)
IMPG1 Interphotoreceptor matrix proteoglycan 1 6q14.1 Xu et al. (2014)
INO80 INO80 complex subunit 15q15.1 Xu et al. (2014)
IQGAP2 IQmotif containing GTPase activating protein 2 5q13.3 Le-Niculescu et al. (2009)
ITGAV Integrin, alpha V 2q32.1 Le-Niculescu et al. (2009)
ITIH3* Inter-alpha-trypsin inhibitor, heavy chain 3 3p21.1 Hamshere et al. (2013)
JAK1 Janus kinase 1 1p31.3 Xu et al. (2014)
JAM3 Junctional adhesion molecule 3 11q25 Baum et al. (2008a, 2008b)
KCNAB1 Potassium channel, voltage gated subfamily A regulatory beta subunit 1 3q25.31 Le-Niculescu et al. (2009)
KCNB1 Potassium channel, voltage gated Shab-related subfamily B, member 1 20q13.2 Le-Niculescu et al. (2009)
KCNC2 Potassium channel, voltage gated Shaw related subfamily C, member 2 12q14.1 Burton et al. (2007)
KCND2# Potassium voltage-gated channel, Shal-related family, member 2 7q31.31 Le-Niculescu et al. (2009)
KCNIP4 Kv channel interacting protein 4 4p15.32 Xu et al. (2014)
KCNK1 Potassium channel, subfamily K, member 1 1q422 Le-Niculescu et al. (2009)
KHDC1 KH homology domain containing 1 6q13 Xu et al. (2014)
KIAA1462 KIAA1462 gene 10p11.23 Xu et al. (2014)
KIF13B Kinesin family member 13B 8p12 Xu et al. (2014)
KLF12 Kruppel-like factor 12 13q22.1 Le-Niculescu et al. (2009)
KIF1A Kinesin family member 1 A 2q37.3 Le-Niculescu et al. (2009)
KLHL3 Kelch-like family member 3 5q312 Cichon et al. (2011)
KLHL20 Kelch-like family member 20 1q25.1 Xu et al. (2014)
LARGE Like-glycosyltransferase 22q12.3 Le-Niculescu et al. (2009)
LDLRAD4 Low density lipoprotein receptor class A domain containing 4 18p11.21 Le-Niculescu et al. (2009)
LEF1 Lymphoid enhancer-binding factor 1 4q25 Le-Niculescu et al. (2009)
LHFPL3 Lipoma HMGIC fusion partner-like 3 7q22.2 Cichon et al. (2011)
LMO7 LIM domain 7 13q22.2 Le-Niculescu et al. (2009)
LMOD3 Leiomodin 3 3p14.1 Xu et al. (2014)
LRRC74A Leucine rich repeat containing 74A 14q24.3 Xu et al. (2014)
LRRFIP1 Leucine rich repeat (In FLII) interacting protein 1 2q37.3 Xu et al. (2014)
LYPD5 LY6/PLAUR domain containing 5 19q13.31 Cichon et al. (2011)
MACROD1 MACRO domain containing 1 11q13.1 Cichon et al. (2011)
MAD1L1* MAD1 mitotic arrest deficient-like 1 (yeast) 7p22.3 Cichon et al. (2011)
MAOA*# Monoamine oxidase A Xp11.3 Fan et al. (2010)
MARCH1 Membrane-associated ring finger (C3HC4) 1, E3 ubiquitin protein ligase 4q32.2 Xu et al. (2014)
MBNL2 Musclebind-like splicing regulator 2 13q32.1 Le-Niculescu et al. (2009)
MBP Myelin basic protein 18q23 Le-Niculescu et al. (2009)
MDH1 Malate dehydrogenase 1, NAD (soluble) 2p13.3 Le-Niculescu et al. (2009)
MFSD11 Major facilitator superfamily domain containing 11 17q25.1 Xu et al. (2014)
MTHFR*# Methylenetetrahydrofolate reductase (NAD(P)H) 1p36.22 El-Hadidy et al. (2014)
MTMR3 Myotubularin related protein 3 22q12.2 Xu et al. (2014)
MYCBP2 MYC binding protein 2, E3 ubiquitin protein ligase 13q22.3 Le-Niculescu et al. (2009)
MYO5B Myosin VB 18q21.1 Sklar et al. (2008)
MYO18B Myosin XVIIIB 22q12.1 Xu et al. (2014)
MYT1L# Myelin transcription factor 1-like 2p25.3 Le-Niculescu et al. (2009)
NAALAD2 N-acetylated alpha-linked acidic dipeptidase 2 11q14.3 Xu et al. (2014)
NALCN* Sodium leak channel, non-selective 13q32.3 Sklar et al. (2008)
NAV2 Neuron navigator 2 11p15.1 Le-Niculescu et al. (2009)
NCALD Neurocalcin delta 8q22.3 Xu et al. (2014)
NCAM1* Neural cell adhesion molecule 1 11q23.2 Le-Niculescu et al. (2009)
NCAN Neurocan 19p12 Cichon et al. (2011)
NCKAP5# NCK-associated protein 5 2q21.2 Smith et al. (2009)
NDUFAB1 NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8 kDa 16p12.2 Burton et al. (2007)
NDUFS2 NADH dehydrogenase (ubiquinone) Fe-S protein 2,49 kDa (NADH-coenzyme Qreductase) 1q23.3 Le-Niculescu et al. (2009)
NFIA# Nuclear factor I/A 1p31.3 Le-Niculescu et al. (2009)
NFIB Nuclear factor I/B 9p24.1 Le-Niculescu et al. (2009)
NIPBL Nipped-B homolog (Drosophila) 5p132 Xu et al. (2014)
NME7 NME/NM23 family member 7 1q24.2 Xu et al. (2014)
NOS1AP*# Nitric oxide synthase 1 (neuronal) adaptor protein 1q23.3 Xu et al. (2014)
NPAS3* Neuronal PAS domain protein 3 14q13.1 Pickard et al. (2009)
NPFFR2 Neuropeptide FF receptor 2 isoform 1 4q13.3 Xu et al. (2014)
NR3C1 Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) 5q31.3 Le-Niculescu et al. (2009)
NRCAM# Neuronal cell adhesion molecule 7q31.1 (Le-Niculescu et al., (2009)
NRG1 *# Neuregulin 1 8p12 Prata et al. (2009)
NRG3* Neuregulin 3 10q23.1 Xu et al. (2014)
NTF3* Neurotrophin 3 12p13.31 Cichon et al. (2011)
NTRK2* Neurotrophic tyrosine kinase, receptor, type 2 9q21.33 Smith et al. (2009)
NUP214 Nucleoporin 214 kDa 9q34.13 Xu et al. (2014)
OC90 Otoconin 90 8q24.22 Xu et al. (2014)
OLIG2* Oligodendrocyte lineage transcription factor 2 21q22.11 Le-Niculescu et al. (2009)
OPRM1 # Opioid receptor, mu 1 6q25.2 Le-Niculescu et al. (2009)
OR1B1 Olfactory receptor, family 1, subfamily B, member 1 9q33.2 Xu et al. (2014)
PALB2 Partner and localizer of BRCA2 16p12.2 Tesli et al. (2010)
PARD3 Par-3 family cell polarity regulator 10p11.21 Le-Niculescu et al. (2009)
PARD3B# Par-3 family cell polarity regulator beta 2q33.3 Cichon et al. (2011)
PCDHAC2# Protocadherin-alpha, subfamily C, 2 5q31.3 Pedrosa et al. (2008)
PCDH7 Protocadherin 7 4p15.1 Le-Niculescu et al. (2009)
PCDH9# Protocadherin 9 13q21.32 Le-Niculescu et al. (2009)
PCLO Piccolo presynaptic cytomatrix protein 7q21.11 Choi et al. (2011)
PDE10A Phosphodiesterase 10 A 6q26 Le-Niculescu et al. (2009)
PDE4B*# Phosphodiesterase 4B, CAMP-specific 1p31.3 Xu et al. (2014)
PER3* Period circadian clock 3 1p3623 Benedetti et al. (2008)
PDLIM5* PDZ and LIM domain 5 4q22.3 Shi et al. (2008)
PHF20 PHD finger protein 20 20q11.22 Xu et al. (2014)
PIK3R1 Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 5q13.1 Le-Niculescu et al. (2009)
PLCL2 Phospholipase C-like 2 3p24.3 Xu et al. (2014)
PLXNA2* Plexin A2 1q32.2 Le-Niculescu et al. (2009)
PPM1B Protein phosphatase, Mg2+/Mn2+ dependent, 1B 2p22.1 Le-Niculescu et al. (2009)
PPP2R2A Protein phosphatase 2, regulatory subunit B, alpha 8p212 Xu et al. (2014)
PPP2R2C Protein phosphatase 2, regulatory subunit B, gamma 4p16.1 Baum et al. (2008a, 2008b)
PRKCE Protein kinase C, epsilon 2p21 Le-Niculescu et al. (2009)
PRPF18 Pre-MRNA processing factor 18 10p12.33 Xu et al. (2014)
PRR16 Proline rich 16 5q23.1 Xu et al. (2014)
PRSS55 Protease, serine, 55 8p23.1 Xu et al. (2014)
PTN Pleiotrophin 7q33 Le-Niculescu et al. (2009)
PTPRK Protein tyrosine phosphatase, receptor type, K 6q22.33 Le-Niculescu et al. (2009)
PTPRM# Protein tyrosine phosphatase, receptor type, M 18p11.23 Le-Niculescu et al. (2009)
PTPRO Protein tyrosine phosphatase, receptor type, O 12p12.3 Xu et al. (2014)
PYDC2 Pyrin domain containing 2 3q28 Cichon et al. (2011)
QKI* Quaking homolog, KH domain RNA binding 6q26 Le-Niculescu et al. (2009)
RABEP1 Rabaptin, RAB GTPase binding effector protein 1 17p13.2 Djurovic et al. (2010)
RABGAP1L RAB GTPase activating protein 1-like 1q25.1 Xu et al. (2014)
RAD51L1 RAD51, paralog B 14q24.1 Xu et al. (2014)
RASGRF2 Ras protein-specific guanine nucleotide-releasing factor 2 5q14.1 Le-Niculescu et al. (2009)
RBFOX1 # RNAbindingprotein, fox-1 homolog (C. elegans) 1 16p13.3 Le-Niculescu et al. (2009)
RBM23 RNA binding motif protein 23 14q11.2 Xu et al. (2014)
RC3H1 Ring finger and CCCH-type domains 1 1q25.1 Xu et al. (2014)
RLF Rearranged L-Myc fusion 1p34.2 Xu et al. (2014)
RORA# RAR-related orphan receptor alpha 15q22.2 Le-Niculescu et al. (2009)
RORB RAR-related orphan receptor beta 9q21.13 Le-Niculescu et al. (2009)
RSPO4 R-spondin 4 20p13 Xu et al. (2014)
RXRG Retinoid × receptor, gamma 1q23.3 Le-Niculescu et al. (2009)
RYR3 Ryanodine receptor 3 15q13.3 Le-Niculescu et al. (2009)
SCAMP1 Secretory carrier membrane protein 1 5q14.1 Le-Niculescu et al. (2009)
SCN7A# Sodium channel, voltage gated, type VII alpha subunit 2q24.3 Xu et al. (2014)
SHISA9 Shisa family member 9 16p13.12 Xu et al. (2014)
SLC39A3 Solute carrier family 39 (Zinc transporter), member 3 19p13.3 Baum et al. (2008a, 2008b)
SLC6A3*# Solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 5p15.33 Greenwood et al. (2006)
SLC8A1 Solute carrier family 8 (sodium/calcium exchanger), member 1 2p22.1 Le-Niculescu et al. (2009)
SOD1 # Superoxide dismutase 1, soluble 21q22.11 Le-Niculescu et al. (2009)
SORCS2 Sortilin-related VPS10 domain containing receptor 2 4p16.1 Soronen et al. (2010)
SPAG16 Sperm associated antigen 16 2q34 Xu et al. (2014)
SPARC Secreted protein, acidic, cysteine-rich (osteonectin) 5q31.3 Le-Niculescu et al. (2009)
SPAST# Spastin 2q22.3 Le-Niculescu et al. (2009)
STAB1 Stabilin 1 3p21.1 Baum et al. (2008a, 2008b)
STK24 Serine/threonin kinase 24 13q32.2 Le-Niculescu et al. (2009)
STX12 Syntaxin 12 1p35.3 Xu et al. (2014)
SVIL Supervillin 10p11.23 Purcell et al. (2009)
SYN3*# Synapsin III 22q12.3 Le-Niculescu et al. (2009)
SYNE1 # Spectrin repeat containing, nuclear envelope 1 6q252 Ferreira et al. (2008)
TBC1D22B TBC1 domain family, member 22B 6p21.2 Xu et al. (2014)
TBXAS1 Thromboxane A synthase 1 7q34 Xu et al. (2014)
TCF4*# Transcription factor 4 18q21.1 Del-Favero et al. (2002)
TEAD1 TEA domain family member 1 11p15.4 Xu et al. (2014)
TENM4 Teneurin transmembrane protein 4 11q14.1 Sklar et al., 2011
TIAM1 T-cell lymphoma invasion and metastasis 1 21q22.11 Le-Niculescu et al. (2009)
TLE4 Transducin-like enhancer ofsplit 4 9q21.31 Cichon et al. (2011)
TMEM252 Transmembrane protein 252 9q21.11 Xu et al. (2014)
TNIK TRAF2 and NCK interacting kinase 3q26.31 Le-Niculescu et al. (2009)
TPH1 Tryptophan hydroxylase 1 11p15.1 Chen et al. (2012)
TPH2*# Tryptophan hydroxylase 2 12q21.1 Cichon et al. (2008)
TPST2 Tyrosylprotein sulfotransferase 2 22q12.1 Le-Niculescu et al. (2009)
TRANK1 Tetratricopeptide repeat and ankyrin repeat containing 1 3p22.2 Mühleisen et al. (2014)
TRIO# Trio rho guanine nucleotide exchange factor 5p15.2 Xu et al. (2014)
TRPM2 Transient receptor potential cation channel, subfamily M, member 2 21q22.3 McQuillin et al. (2006)
TRPM3 Transient receptor potential cation channel, subfamily M, member 3 9q21.12 Le-Niculescu et al. (2009)
TRPV3 Transient receptor potential cation channel, subfamily V member 3 17p13.2 Cichon et al. (2011)
TRRAP Transformation/transcription domain-associated protein 7q22.1 Xu et al. (2014)
TSHZ2 Teashirt zinc finger homeobox 2 20q13.2 Le-Niculescu et al. (2009)
TSPAN8 Tetraspanin 8 12q21.1 Scholz et al. (2010)
VAMP7 Vesicle-associated membrane protein 7 Xq28 or Yq12 Saito et al. (2000)
VIP# Vasoactive Intestinal Peptide 6q252 Soria et al. (2010)
WDR60 WD repeat domain 60 7q36.3 Xu et al. (2014)
WDR7 WD repeat domain 7 18q21.31 Xu et al. (2014)
WNK2 WNK lysine deficient protein kinase 2 9q22.31 Cichon et al. (2011)
XBP1* X box-binding protein 1 22q12.1 Kakiuchi et al. (2003)
XKR4* XK, Kell blood group complex subunit-related family, member 4 8q12.1 Djurovic et al. (2010)
XXYLT1 Xyloside xylosyltransferase 1 3q29 Xu et al. (2014)
ZEB2* Zinc finger E-box binding homeobox 2 2q22.3 Cichon et al. (2011)
ZBTB20# Zinc finger and BTB domain containing 20 3q13.31 Xu et al. (2014)
ZDHHC14 Zinc finger, DHHC-type containing 14 6q25.3 Le-Niculescu et al. (2009)
ZHX2 Zinc fingers and homeoboxes 2 8q24.13 Le-Niculescu et al. (2009)
ZNF274 Zinc finger protein 274 19q13.43 Xu et al. (2014)
ZNF385D* Zinc finger protein 385D 3p24.3 Xu et al. (2014)
ZNF536 Zinc finger protein 536 19q13.11 Djurovic et al. (2010)
ZNF618 Zinc finger protein 618 9q33.1 Cichon et al. (2011)
ZNF804A*# Zinc finger protein 804 A 2q32.1 Williams et al.(2011)
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*

denotes BPD genes that overlap with clinically relevant genes for schizophrenia.

#

denotes BPD genes that overlap with clinically relevant genes for autism spectrum disorder.

Table 2.

Distribution of bipolar disorder (BPD) genes among chromosomes.

Chromosome Total Proportion of total BPD genes P arm Q arm
1 24 8.3% 12 12
2 23 7.9% 6 17
3 18 6.2% 9 9
4 16 5.5% 5 11
5 18 6.2% 4 14
6 18 6.2% 6 12
7 20 6.9% 5 15
8 10 3.4% 5 5
9 19 6.6% 4 15
10 11 3.8% 8 3
11 18 6.2% 7 11
12 8 2.8% 3 5
13 11 3.8% NA 11
14 7 2.4% NA 7
15 7 2.4% NA 7
16 9 3.1% 6 3
17 5 1.7% 2 3
18 11 3.8% 5 6
19 8 2.8% 4 4
20 5 1.7% 1 4
21 7 2.4% NA 7
22 12 4.1% NA 12
X 3 1.0% 2 1
Y 0 0.0% 0 0
Both X and Y 2 0.7% NA NA
Total 290 100% 94 194
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Total number of BPD genes were counted for each chromosome and chromosome arm.

p = short arm; q = long arm.

NA = not applicable due to chromosome structure or location.

The majority of the genes listed in Table 1 are located on chromosomes 1, 2, 3, 4, 5 6, 7, 8, 9, 10, 11, 13, 16, 18, and 22 in accordance with previous reports examining polymorphisms and chromosomal breakpoints of known and candidate genes for BPD (Potash and DePaulo, 2000; Etain et al., 2012). One of the smallest chromosomes (i.e., 22) contained more BPD genes in relationship to its size (i.e., 4.1%) than other comparable chromosomes. The X chromosome which accounts for about 5.6% of the genome contained only 1.0% of the BPD genes. The genes identified in our investigation impacted a broad range of biological pathways and processes including cellular signaling pathways for cAMP and calcium (e.g., CACNA1C, CAMK2A, CAMK2D, ADCY1, ADCY2); glutamatergic (e.g., GRIK1, GRM3, GRM7), dopaminergic (e.g., DRD2, DRD4, COMT, MAOA) and serotonergic (e.g., HTR1A, HTR2A, HTR3B) neurotransmission; molecular transporters (e.g., SLC39A3, SLC6A3, SLC8A1); and neuronal growth (e.g., BDNF, IGFBP1, NRG1, NRG3). These gene classes influence neurotransmission and psychological functioning through direct and indirect effects on neuronal activity, growth, development, maintenance and remodeling. These genes overlap with biological markers and genetic factors associated with other psychiatric disorders such as schizophrenia, (e.g., BDNF, CACNA1, DISC1), major depressive and anxiety disorders (e.g., TPH2, HTR2A) involving developmental processes (e.g., NRG1, NRG3).

4. Discussion

The advent of genetic testing to identify the predisposition for BPD has increased understanding of the genetic etiology of BPD and the application of genetic testing should facilitate research and treatment development. We illustrated a master list of susceptibility genes and genes that are associated with BPD in our results by plotting the individual genes on high-resolution chromosome ideograms and generated a tabular form with references in order to inform more individuals about the necessity for genetic testing and treatment for BPD.

The transmission of BPD does not appear to manifest through a simple Mendelian inheritance with a single allele (dominant) or two alleles (recessive) pattern instead showing incomplete penetrance, etiological heterogeneity and high prevalence (Kerner, 2015). Similarly, multivariate threshold models conceptualized as an accumulation of traits normally distributed throughout the genome are not strongly supported to achieve some threshold for expression. Rather, BPD appears to be a product of a combination of genetic, neurochemical, and environmental influences. The expression or development of bipolar disorder may be due to epistasis (interaction of multiple genes) or other complex mechanisms such as genomic imprinting or dynamic mutations with environmental contributions (Craddock and Jones, 1999). An intricate oligogenic quasi-Mendelian pattern has been proposed whereby a small number of mutations accumulate in a select biological pathway that is only tied to expression of the phenotype when released by environmental influences (Kerner, 2015). Symptoms of bipolar disorder parallel other genetically influenced psychiatric disorders including schizophrenia, depression and anxiety (Krishnan, 2005) and is, not surprisingly, impacted by overlapping genetic constructs (e.g., BDNF, DISC1, HTR2A, TPH2).

Our list of genes for BPD reflects the current status of recognized genes with clinical relevance but susceptibility and new genes are continually being identified. Not all genes in the list are equally significant or certainly causative for all individuals with BPD. Similarly, our results reflect gene-level associations and do not provide evidence of individual SNP- or CNV-level contributions to pathology. The list is particularly suited to the evaluation of structural genomic data (e.g., DNA microarrays) for copy number variations impacting genomic regions and genes of interest which may involve large regions and multiple candidate genes or encompass known genetic syndromes. Phenotype and severity can be predicted to be proportional to the number of candidate genes impacted by the CNV – highlighting the clinical value of spatial representation of the gene list and whether the region is duplicated or deleted. The effect of any individual SNP depends upon both the physiological relevance of the gene to neurodevelopmental processes and the impact of the specific sequence variation or mutation on the expression and function of the gene product (i.e., synonymous vs. non-synonymous). Non-synonymous variations leading to a change of the codon or reading frame (e.g., frameshift mutation, stop codon generation) have greater predicted impact on gene expression and thus stronger ties to pathology. Advances in genomic technology will facilitate the identification and characterization of novel SNPs among the gene candidates and improve understanding of the relative contributions of selected SNP or CNVs to the general disease prevalence.

Combinations of single nucleotide polymorphisms (SNPs) which alter the genetic code, creating a higher likelihood of developing bipolar disorder, are reportedly more common than chromosomal breakpoints at the susceptibility regions for BPD. For example, SNPs within the brain derived neurotrophic factor (BDNF) gene, located in the 11p14, region are reported to result in a modification of the processing and trafficking of the BDNF gene and increased susceptibility to BPD (Craddock et al., 2005). The ABCA13 gene was also identified as a candidate gene for both bipolar and schizophrenia disorders once it was initially discovered by a chromosome abnormality in a schizophrenic patient (Knight et al., 2009). The ABCA13 gene was then resequenced and multiple rare coding variants identified. These variants were genotyped in bipolar cohorts, which led to the conclusion that 4.0% of the population contained a variant which could contribute to bipolar disorder (Knight et al., 2009). Multiple genome-wide association studies (GWAS) testing for SNPs in independent bipolar cases and controls often generate strong signals for gene associations with bipolar disorder (Sklar et al., 2011). For example, results from the first GWAS for BPD reported in 2007 determined that the strongest signals for an association were found in five genes: BDNF at 11p14, DAOA at 13q33, DTNBP1 at 6p22, DISC1 at 1q42, and NRG1 at 8p12, and the SNP rs420259 at 16p12 (Burton et al., 2007). Since this initial study, additional GWAS reports (e.g., Sklar et al., 2008; Ferreira et al., 2008) and a collection of genetic studies examining bipolar disorder did implicate genes that were consolidated in 2014 by Shinozaki and Potash (Shinozaki and Potash, 2014) with a list of candidate genes summarized from 15 studies (e.g., Baum et al., 2008a, 2008b; Sklar et al., 2011; Ou et al., 2015). These genes overlapped with biological markers and genetic factors associated with other psychiatric disorders such as schizophrenia, (e.g., BDNF, CACNA1, DISC1), major depressive and anxiety disorders (e.g., TPH2, HTR2A) and involved in developmental processes.

Our list of candidate genes and visual representation of their locations on high-resolution chromosome ideograms for bipolar disorder provide an informative perspective of the pathophysiology of BPD to facilitate research, accurate diagnosis and genetic counseling, treatment development and classification of BPD (Craddock and Jones, 1999). The authors encourage the use of this collection of currently associated recognized susceptibility genes for BPD in the evaluation of patients presenting for genetic services and for a more accurate understanding of the role of genetics in BPD, a genetically heterogeneous disorder.

Acknowledgments

We thank Lorie Gavulic for excellent artistic design and preparation of chromosome ideograms and Maaz Hassan for assistance in manuscript preparation.

Financial support

This work was supported by the Consortium for Translational Research on Aggression and Drug Abuse and Dependence (ConTRADA) (grant QB864900) and the National Institute of Child Health and Human Development (NICHD) (grant HD02528).

Abbreviations:

BPD

bipolar disorder

BP-I

Bipolar I Disorder

BP-II

Bipolar II Disorder

BP-NOS

Bipolar Disorder Not Otherwise Specified

cAMP

cyclic adenosine monophosphate

DNA

deoxyribonucleic acid

DSM-5

Diagnostic and Statistical Manual for Mental Disorders, fifth edition

FDA

Food and Drug Administration

GWAS

genome-wide association studies

OMIM

online Mendelian inheritance in man

SNPs

single nucleotide polymorphisms

Footnotes

Conflicts of interest

The authors declare no conflict of interest.

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