Abstract
BackgroundRecently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).MethodsHere we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.ResultsAlthough no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.ConclusionsThe findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.
Highlights
Genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD)
Quality-control (QC) procedures were applied to the 510,740 single nucleotide polymorphisms (SNPs) in the discovery dataset and 440,794 SNPs in the validation dataset
Population stratification After applying quality control (QC) filters, 502,877 common autosomal SNPs remained in the discovery dataset and 346,565 common autosomal SNPs remained in the validation dataset
Summary
Genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD). Bipolar disorder (BD), known as manic-depressive illness, is a chronic and devastating psychiatric condition, affecting 0.5-1.6% of the general population across their lifetime [1]. The frequency of hospitalization, psychological impairment, family devastation and suicidal behaviour make BD a major public health concern [2,3], with an estimated total annual societal cost of at least 45 billion dollars in North America [4]. It is characterized by the recurrence of manic and hypomanic episodes. The recurrence risk in siblings of a BD proband is ~8% (corresponding to a sibling relative risk compared with the general population of λS ~ 8), and for monozygotic (identical) co-twins the risk is ~ 60%
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