Whole-genome association study of bipolar disorder

Abstract

We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the University College London sample collections with successful genotyping for 372 193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P = 1.66 Â 10 À7 ) and tetraspanin-8 (TSPAN8; P = 6.11 Â 10 À7 ). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P = 2.04 Â 10 À8 , TSPAN8; P = 7.57 Â 10 À7 and EGFR; P = 8.36 Â 10 À8 ). For replication, we genotyped 304 SNPs in family-based NIMH samples (n = 409 trios) and University of Edinburgh case-control samples (n = 365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case-Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.

European collaborative study of early‐onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

“…The region has been identified in three previous genome scans Fallin et al, 2004;Pato et al, 2004) and by the meta-analysis reported by Segurado et al (Segurado et al, 2003); note that none of these studies considered AAO in their analyses. One of the four genome-wide association studies conducted for bipolar disorder (WTCCC, 2007;Baum et al, 2008, Sklar et al, 2008, the Wellcome Trust Case control consortium, reported moderate evidence for association of bipolar disorder in the 2q14 region (p=10 -6 ). This region however gave no or only weak signals for association in the three other studies.…”

“…However, such findings have not always been replicated (Craddock and Forty, 2006), and meta-analysis of 18 genome scans on bipolar disorder failed to yield statistically significant linkage results (Segurado et al, 2003). Recently, three groups have performed independent whole genome association studies of bipolar disorder (WTCCC, 2007;Baum et al, 2008;Sklar et al, 2008), but the studies agreed only for a limited number of regions and for the ankyrin 3 (ANK3) O'Donovan et al, 2009;Smith et al, 2009;Schulze et al, 2009;Scott et al, 2009;Moskvina et al, 2009) gene and alpha 1C subunit of the voltage-dependent calcium channel (CACNA1C) O'Donovan et al, 2009) genes. This may reflect clinical and genetic heterogeneity of bipolar disorder and lack of a consensus definition for the affected phenotype Leboyer, 2003 A "symptom candidate approach" has been proposed to disentangle the genetic and clinical heterogeneity of BP, and age at onset (AAO) has proved to be a relevant candidate symptom .…”

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…Large scale collaborative genome‐wide association studies (GWAS) have identified a number of risk loci significantly associated with bipolar disorder (BP), including ODZ4 [Sklar et al, 2011; Muhleisen et al, 2014], CACNA1C [Ferreira et al, 2008; Sklar et al, 2008], ANK3 [Ferreira et al, 2008; Schulze et al, 2009; Muhleisen et al, 2014], NCAN [Cichon et al, 2011], C15ORF53 [Ferreira et al, 2008], and DGKH [Baum et al, 2008a,2008b]. Individually, each of those genes/loci contributes only a small fraction toward overall disease risk, typically <1% of the phenotypic variance [Ferreira et al, 2008].…”

The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

“…Effect of genetic variants in CACNA1D on insulin secretion and type 2 diabetes The expression of the related L-VGCC gene CACNA1C has been shown to be genetically determined by SNPs [35], giving a functional explanation for associations of CACNA1C genotypes with neurological disorders [36,37]…”