Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case-control sample.
We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10(-3) from the BD meta-analysis by Ferreira et al. were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=4.09 × 10(-4)) and 15q14 (rs2172835, P=0.043) but not ANK3 (rs10994336, P=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel GWS associations. First, rs7296288 (P=8.97 × 10(-9), odds ratio (OR)=0.9), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH. Second, rs3818253 (P=3.88 × 10(-8), OR=1.16), an intronic SNP on chromosome 20q11.2 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B.
Department of Psychological Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Heath Park, Cardiff, UK.
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EK
Green
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Hamshere
L
L
Forty
K
K
Gordon-Smith
C
C
Fraser
E
E
Russell
D
D
Grozeva
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G
Kirov
P
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Holmans
J L
JL
Moran
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Purcell
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Sklar
M J
MJ
Owen
M C
MC
O'Donovan
L
L
Jones
I R
IR
Jones
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Craddock
D000483:Alleles; D017487:Ankyrins / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics*; D020746:Calcium Channels, L-Type / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
C490613:ANK3 protein, human; D017487:Ankyrins; C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type