Article

Genome-Wide Association Study of Major Recurrent Depression in the UK Population

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
American Journal of Psychiatry (Impact Factor: 12.3). 08/2010; 167(8):949-57. DOI: 10.1176/appi.ajp.2010.09091380
Source: PubMed

ABSTRACT

Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders.
Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry.
Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1.
This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.

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    • "A meta-analysis of twin studies showed that the heritability of MDD averages 37% [Sullivan et al., 2000]. However, results from linkage studies have been inconsistent [Holmans et al., 2004; McGuffin et al., 2007] and almost all large-scale genomewide association studies (GWAS) for MDD failed to detect genes at genome-wide significance level [Lewis et al., 2010; Muglia et al., 2010; Rietschel et al., 2010; Shi et al., 2011]. Moreover, candidate gene studies have been only marginally successful. "

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    • "Deterministic genetic models for psychiatric illness have proved elusive. Genome-wide association studies (GWAS) have not translated into significant therapeutic gains for disorders such as depression, and aetiology from a genetic viewpoint remains opaque (Lewis et al. 2010; Ripke et al. 2013). Possible reasons for this include well-cited nosological difficulties (Casey et al. 2013) incorporating phenomenological, psychopathological and pathophysiological heterogeneity, small effect sizes of individual genes and overestimated heritability (McGuffin et al. 2007; Bohacek & Mansuy, 2013; Uher, 2014). "
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    • ") appeared , not a single biological test was ready for inclusion in the DSM - 5 over three decades later ( Kapur et al . , 2012 ) . Large genome - wide asso - ciation studies have been unable to replicate genetic associations with depression diagnosis ( Lewis et al . , 2010 ; Shi et al . , 2011 ; Wray et al . , 2012 ; Daly et al . , 2013 ) or treatment response ( Tansey et al . , 2012 ) , and in a recent study with over 34000 subjects , no single locus reached genome - wide significance ( Hek et al . , 2013 ) . The high comorbidity rates of depression with other disorders such as generalized anxiety disord"
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