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 x 10(-7)) and tetraspanin-8 (TSPAN8; P=6.11 x 10(-7)). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 x 10(-8), TSPAN8; P=7.57 x 10(-7) and EGFR; P=8.36 x 10(-8)). 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.

Figure 1

Plot of MYO5B, TSPAN8 and EGFR regions of association. Association results (−log10 p) are plotted for all SNPs passing QC in the combined STEP-BD and UCL sample. A) MYO5B, B) TSPAN8, and C) EGFR. Chromosome position is plotted with reference to the NCBI build 35 and gene names are plotted with reference to the University of California at Santa Cruz Genome Browser. Recombination rate as estimated from the HapMap is plotted in light blue. Blue diamond: SNP with strongest evidence for association. Red diamonds: strength of LD with blue diamond SNP (darker red indicates stronger LD).

Figure 2

Plot of CACNA1C region of association. Association results (−log10 p) are plotted for all SNPs passing QC. A) Combined STEP-BD and UCL samples, and B) WTCCC. See Figure 1 for description of plots.