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Clock genes may influence bipolar disorder susceptibility and dysfunctional circadian rhythm
Author(s) -
Shi Jiajun,
WittkeThompson Jacqueline K.,
Badner Judith A.,
Hattori Eiji,
Potash James B.,
Willour Virginia L.,
McMahon Francis J.,
Gershon Elliot S.,
Liu Chunyu
Publication year - 2008
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30714
Subject(s) - circadian rhythm , biology , genetics , transmission disequilibrium test , timeless , clock , circadian clock , haplotype , single nucleotide polymorphism , per1 , candidate gene , gene , genotype , endocrinology
Several previous studies suggest that dysfunction of circadian rhythms may increase susceptibility to bipolar disorder (BP). We conducted an association study of five circadian genes ( CRY2 , PER1‐3 , and TIMELESS ) in a family collection of 36 trios and 79 quads (Sample I), and 10 circadian genes ( ARNTL , ARNTL2 , BHLHB2 , BHLHB3 , CLOCK , CRY1 , CSNK1D , CSNK1E , DBP , and NR1D1 ) in an extended family collection of 70 trios and 237 quads (Sample II), which includes the same 114 families but not necessarily the same individuals as Sample I. In Sample II, the Sibling‐Transmission Disequilibrium Test (sib‐tdt) analysis showed nominally significant association of BP with three SNPs within or near the CLOCK gene (rs534654, P = 0.0097; rs6850524, P = 0.012; rs4340844, P = 0.015). In addition, SNPs in the ARNTL2 , CLOCK , DBP , and TIMELESS genes and haplotypes in the ARNTL , CLOCK , CSNK1E , and TIMELESS genes showed suggestive evidence of association with several circadian phenotypes identified in BP patients. However, none of these associations reached gene‐wide or experiment‐wide significance after correction for multiple‐testing. A multi‐locus interaction between rs6442925 in the 5′ upstream of BHLHB2 , rs1534891 in CSNK1E , and rs534654 near the 3′ end of the CLOCK gene, however, is significantly associated with BP ( P = 0.172). It remains significant after correcting for multiple testing using the False Discovery Rate method. Our results indicate an interaction between three circadian genes in susceptibility to bipolar disorder. © 2008 Wiley‐Liss, Inc.