Molecular Genetic Analysis Subdivided by Adversity Exposure Suggests Etiologic Heterogeneity in Major Depression

Abstract

Objective: The extent to which major depression is the outcome of a single biological mechanism or represents a final common pathway of multiple disease processes remains uncertain. Genetic approaches can potentially identify etiologic heterogeneity in major depression by classifying patients on the basis of their experience of major adverse events.

Method: Data are from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology (CONVERGE) project, a study of Han Chinese women with recurrent major depression aimed at identifying genetic risk factors for major depression in a rigorously ascertained cohort carefully assessed for key environmental risk factors (N=9,599). To detect etiologic heterogeneity, genome-wide association studies, heritability analyses, and gene-by-environment interaction analyses were performed.

Results: Genome-wide association studies stratified by exposure to adversity revealed three novel loci associated with major depression only in study participants with no history of adversity. Significant gene-by-environment interactions were seen between adversity and genotype at all three loci, and 13.2% of major depression liability can be attributed to genome-wide interaction with adversity exposure. The genetic risk in major depression for participants who reported major adverse life events (27%) was partially shared with that in participants who did not (73%; genetic correlation=+0.64). Together with results from simulation studies, these findings suggest etiologic heterogeneity within major depression as a function of environmental exposures.

Conclusions: The genetic contributions to major depression may differ between women with and those without major adverse life events. These results have implications for the molecular dissection of major depression and other complex psychiatric and biomedical diseases.

Keywords: Diagnosis and Classification; Genetics; Mood Disorders-Unipolar.

Figure 1

Manhattan plots of loci associated with major depression. (a) Manhattan plot of major depression for all subjects for whom information on exposure to adversity is available; (b) Manhattan plot of major depression in a subgroup reporting exposure to adversity; (c) Manhattan plot of major depression in a subgroup reporting no exposure to adversity. In each plot, the -log10 P-values of imputed SNPs associated with major depression by leave-one-chromosome-out linear mixed model association in BOLT-LMM are shown on the left y axes. The horizontal axis gives the position on each chromosome; chromosomes are numbered below the axis.

Figure 2

Genes at three loci associated with major depression in the subgroup reporting no adversity. (a) Locus on chromosome 1, 212 Mb, over the gene encoding lysophosphatidylglycerol acyltransferase 1 (LPGAT1) (peak SNP = rs7526682,); (b) Locus on chromosome 1, 226 Mb, over the gene C1ORF95 (peak SNP = rs11577545); (c) Locus on chromosome 8 at 23.4Mb, over the 3′ end of the mitoferrin gene SLC25A37 (peak SNP = rs950893). The -log10 P-values of imputed SNPs associated with major depression by logistic regression are shown on the left y axes together the recombination rates (NCBI Build GRCh37), represented by light-blue lines, with scales on the right y axes. Genes within the regions are shown in the bottom panels. The horizontal axis gives the chromosomal position in megabases (Mb). The index SNPs are shown as larger purple diamonds labeled by their marker names; linkage disequilibrium (hg19 1000 Genomes ASN panel Nov 2014) with the remaining SNPs is indicated by different colors.