期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：3576-3581
DOI：10.1073/pnas.1424958112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceBipolar disorder (BD) is a common, severe, and recurrent psychiatric disorder with no known cure and substantial morbidity and mortality. Heritable causes contribute up to 80% of the lifetime risk for BD. Common genetic variation explains [~]25% of this heritable risk. Rare genetic variants may explain additional risk. We identified contributions of rare variants to BD by sequencing the genomes of 200 individuals from 41 families with BD. The two main findings of this study were as follows: rare risk variants for BD were enriched in genes and pathways that regulate diverse aspects of neuronal excitability; and most of these risk variants were noncoding with predicted regulatory functions. These results highlight specific hypotheses for future research and potential therapeutic targets. We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.
