Abstract
The recent success of a large genome-wide association (GWA) study—analysing 130 620 major depression cases and 347 620 controls—in identifying the first single-nucleotide polymorphism (SNP) loci robustly associated with major depression in Europeans confirms that immense sample sizes are required to identify risk loci for depression. Given the phenotypic similarity between major depressive disorder (MDD) and the less severe minor depressive disorder (MiDD), we hypothesised that broadening the case definition to include MiDD may be an efficient approach to increase sample sizes in GWA studies of depression. By analysing two large twin pair cohorts, we show that minor depression and major depression lie on a single genetic continuum, with major depression being more severe but not aetiologically distinct from minor depression. Furthermore, we estimate heritabilities of 37% for minor depression, 46% for major depression and 48% for minor or major depression in a cohort of older adults (aged 50–92). However, the heritability of minor or major depression was estimated at 40% in a cohort of younger adults (aged 23–38). Moreover, two robust major depression-risk SNPs nominally associated with major depression in our Australian GWA data set produced more significant evidence for association with minor or major depression. Hence, broadening the case phenotype in GWA studies to include subthreshold definitions, such as MiDD, should facilitate the identification of additional genetic risk loci for depression.
Highlights
IntroductionEuropean samples have failed to robustly identify genetic variants contributing to Major depressive disorder (MDD).[2,3,4,5,6,7,8,9,10,11] In July 2015, two genome-wide significant (Po 5 × 10 − 8) single-nucleotide polymorphism (SNP) loci (rs12415800 near the SIRT1 gene, P = 2.53 × 10 − 10, and rs35936514 in the intron of LHPP, P = 6.45 × 10 − 12) were reported to be associated with severe and recurrent MDD in a sample of Han Chinese women (5282 cases and 5220 controls);[12] these
Findings from the present study of two independent twin cohorts indicate the heritability of minor depression has a genetic contribution
The genetic heritability of minor depression appears larger in the over 50’s cohort compared to the Twin cohort (TE) cohort
Summary
European samples have failed to robustly identify genetic variants contributing to MDD.[2,3,4,5,6,7,8,9,10,11] In July 2015, two genome-wide significant (Po 5 × 10 − 8) single-nucleotide polymorphism (SNP) loci (rs12415800 near the SIRT1 gene, P = 2.53 × 10 − 10, and rs35936514 in the intron of LHPP, P = 6.45 × 10 − 12) were reported to be associated with severe and recurrent MDD in a sample of Han Chinese women (5282 cases and 5220 controls);[12] these. An important implication of this study is that immense sample sizes are required to identify a relatively modest number of MDD risk loci in Europeans (compared to other traits of similar prevalence and heritability).[14]
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