Meta-analysis of genome-wide association studies of anxiety disorders.
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Otowa T, Hek K, Lee M, Byrne E M, Mirza S S, Nivard M G, Bigdeli T, Aggen S H, Adkins D, Wolen A, Fanous A, Keller M C, Castelao E, Kutalik Z, Van der Auwera S, Homuth G, Nauck M, Teumer A, Milaneschi Y, Hottenga J-J, Direk N, Hofman A, Uitterlinden A, Mulder C L, Henders A K, Medland S E, Gordon S, Heath A C, Madden P A F, Pergadia M L, van der Most P J, Nolte I M, van Oort F V A, Hartman C A, Oldehinkel A J, Preisig M, Grabe H J, Middeldorp C M, Penninx B W J H, Boomsma D, Martin N G, Montgomery G, Maher B S, van den Oord E J, Wray N R, Tiemeier H, Hettema J M
Аннотация
Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.