We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10−7). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.
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We would like to recognize the contribution of thousands of subjects without whom this work would not be possible. T. Lehner (National Institute of Mental Health (NIMH)) was instrumental in initiating and planning the overall project. D. Posthuma and the Dutch Genetic Cluster Computer provided invaluable computational resources. We also thank the PGC schizophrenia group for allowing us to perform the combined analyses of six loci before publication. This work was supported by many grants from the US National Institutes of Health (NIH) (MH078151, MH081804, MH059567 supplement, MH59553, MH080372 and 1U54RR025204). Other sources of support include: the Genetic Association Information Network (GAIN), the NIMH Intramural Research Program, the Tzedakah Foundation, the American Philosophical Society, the Stardust foundation, the National Library of Medicine, the Stanley Medical Research Institute, the Merck Genome Research Institute and the Wellcome Trust, the Pritzker Neuropsychiatric Disorders Research Fund L.L.C., GlaxoSmithKline, as well as grants for individual studies (see the Supplemental Note for a full list of Acknowledgements). The TOP Study was supported by grants from the Research Council of Norway (167153/V50, 163070/V50 and 175345/V50), the South-East Norway Health Authority (123-2004) and the EU (ENBREC). Additional acknowledgments can be found in the Supplementary Note.
Genotype data from this manuscript for the 10,257 samples can be obtained from the Center on Collaborative Genetic Studies of Mental Disorders in accordance with NIMH data release policies (http://zork.wustl.edu/nimh/). Genotype data from the WTCCC sample can be obtained from https://www.wtccc.org.uk/info/access_to_data_samples.shtml. Genotype data from the BOMA-Bipolar Study can be obtained by contacting S. Cichon directly (email@example.com).
The author declare no competing financial interests.
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