Meta-analysis of genome-wide association studies of anxiety disorders

T Otowa, Karin Hek, Max Lee, EM Byrne, Saira Mirza, MG Nivard, T Bigdeli, SH Aggen, D Adkins, A Wolen, A Fanous, MC Keller, E Castelao, Z Kutalik, SV der Auwera, G Homuth, M Nauck, A Teumer, Y Milaneschi, JJ HottengaNese Direk, Bert Hofman, André Uitterlinden, Niels Mulder, AK Henders, SE Medland, S Gordon, AC Heath, PAF Madden, ML Pergadia, PJ van der Most, IM Nolte, Floor Oort, CA Hartman, AJ Oldehinkel, M Preisig, HJ Grabe, CM Middeldorp, BWJH Penninx, D Boomsma, NG Martin, G Montgomery, BS Maher, EJ van den Oord, NR Wray, Henning Tiemeier, JM Hettema

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Abstract

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 x 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P = 2.86 x 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.
Original languageUndefined/Unknown
Pages (from-to)1391-1399
Number of pages9
JournalMolecular Psychiatry
Volume21
Issue number10
DOIs
Publication statusPublished - 2016

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