Abstract
Gene × environment (G × E) interactions mediating depressive symptoms have been separately identified in the stress-sensitive serotonergic (5-HTTLPR) and corticotropin-releasing hormone (CRHR1) systems. Our objective was to examine whether the effects of child abuse are moderated by gene × gene (G × G) interactions between CRHR1 and 5-HTTLPR polymorphisms. We used an association study examining G × G × E interactions of CRHR1 and 5-HTTLPR polymorphisms and measures of child abuse on adult depressive symptomatology. The participant population (N = 1,392) was African-American, of low socioeconomic status (60% with <$1,000/month family income), and with high rates of childhood and lifetime trauma. Depressive symptoms were measured with Beck Depression Inventory (BDI) and history of Major Depression by Structure Clinical Interview based on DSM-IV (SCID). We first replicated an interaction of child abuse and 5-HTTLPR on lifetime SCID diagnosis of major depression in a subsample (N = 236) of the study population—the largest African-American 5-HTTLPR cohort reported to date. We then extended our previously reported interaction with both a CRHR1 SNP (rs110402) and TCA haplotype interacting with child abuse to predict current symptoms (N = 1,059; P = 0.0089). We found that the 5-HTTLPR S allele interacted with CRHR1 haplotypes and child abuse to predict current depressive symptoms (N = 856, P = 0.016). These data suggest that G × E interactions predictive of depressive symptoms may be differentially sensitive to levels of childhood trauma, and the effects of child abuse are moderated by genetic variation at both the CRHR1 and 5-HTTLPR loci and by their G × G interaction. © 2009 Wiley-Liss, Inc.
Highlights
Epidemiological and molecular genetic data have established that both environmental and genetic factors contribute to the risk of major depression, with heritability estimates ranging between 30% and 40%, with the remaining variance influenced by mostly individual specific environmental factors [Kendler, 1995; Levinson, 2006]
We have recently reported an interaction of child abuse with polymorphisms in the type 1 CRF receptor gene, CRHR1, to predict adult depression in two independent cohorts [Bradley et al, 2008]
For CRHR1 variants, we investigated the effects of the best Single-Nucleotide Polymorphisms (SNP) from Bradley et al [2008], rs110402 using a protective allele carrier model (AA and AG vs. GG—see Table II) and a carrier model of the protective haplotype described in this article
Summary
Epidemiological and molecular genetic data have established that both environmental and genetic factors contribute to the risk of major depression, with heritability estimates ranging between 30% and 40%, with the remaining variance influenced by mostly individual specific environmental factors [Kendler, 1995; Levinson, 2006]. Two large genome-wide association studies for unipolar depression have been published, which reported more or less negative results for larger main genetic effects [Muglia et al, 2008; Sullivan et al, 2008]. Both studies were case–control associations, and neither included environmental exposure as a factor nor investigated gene  gene (G  G) interactions. Genome-wide G  E or gene  gene  environment (GÂGÂE) studies for unipolar depression have, to the best of our knowledge, not yet been conducted and would require very large sample sizes to attain sufficient power. We focus on a candidate GÂGÂE interaction
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