a survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response基因组研究的调查支持协会的生物钟基因与双相情感障碍谱系疾病和锂的反应.pdfVIP

A Survey of Genomic Studies Supports Association of Circadian Clock Genes with Bipolar Disorder Spectrum Illnesses and Lithium Response Michael J. McCarthy1,2,3*, Caroline M. Nievergelt2,3, John R. Kelsoe1,2,3, David K. Welsh1,2,3 1Veterans Affairs San Diego Healthcare System, San Diego, California, United Sates of America, 2 Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America, 3 Center for Chronobiology, University of California San Diego, La Jolla, California, United States of America Abstract Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian ‘‘clock genes’’ associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential ‘‘core’’ clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium- responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were