In this study, measures of the quality and availability of social supports were found to moderate risk for depression associated with a history of maltreatment and the presence of the short (s) allele of the serotonin transporter gene promoter polymorphism (5-HTTLPR). The present investigation (i) replicates research in adults showing that 5-HTTLPR variation moderates the development of depression after stress, (ii) extends the finding to children, and (iii) demonstrates the ability of social supports to further moderate risk for depression. Maltreated children with the s͞s genotype and no positive supports had the highest depression ratings, scores that were twice as high as the non-maltreated comparison children with the same genotype. However, the presence of positive supports reduced risk associated with maltreatment and the s͞s genotype, such that maltreated children with this profile had only minimal increases in their depression scores. These findings are consistent with emerging preclinical and clinical data suggesting that the negative sequelae associated with early stress are not inevitable. Risk for negative outcomes may be modified by both genetic and environmental factors, with the quality and availability of social supports among the most important environmental factors in promoting resiliency in maltreated children, even in the presence of a genotype expected to confer vulnerability for psychiatric disorder.child maltreatment ͉ gene-by-environment interaction C hild abuse is a pervasive societal problem, with nearly 1 million substantiated reports of child maltreatment each year (1), many reported cases of actual abuse that are not verified (2), and countless other cases that never come to the attention of authorities (3). Although not all abused children develop difficulties, many experience a chronic course of psychopathology, with depression as one of the most common psychiatric sequelae reported in maltreated children (4, 5).Preclinical studies suggest that stress early in life can promote long-term changes in multiple neurochemical systems (6, 7). Specifically, exposure to prenatal and͞or postnatal stress is associated with increased basal and stress-induced responsiveness of the hypothalamic pituitary adrenal axis, increased central corticotropin-releasing hormone and norepinephrine drive, decreased ␥-aminobutyric acid͞benzodiazepine functioning, multiple alterations in the serotonergic system, and reduction in hippocampal volume, a brain structure vulnerable to the neurotoxic effects of stress-induced elevations in circulating glucocorticoids (e.g., cortisol) and amino acids (e.g., glutamate).Because many of the biological alterations associated with early stress in preclinical studies have been reported in adults with depression, it has been hypothesized that the neurobiological changes associated with adverse early experiences may confer a vulnerability for the development of depression (6,8). Consistent with preclinical studies, adults with depression have been reported to have multiple ...

No abstract

Conflict of interest statement: No conflicts declared.Freely available online through the PNAS open access option.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM-IV diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case/control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E-13) and African ancestries (rs2066702; p = 2.2E-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, ADHD, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non-pathological drinking behaviors.

We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus, showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P = 1.17 × 10−31; AAs: Arg369Cys, P = 6.33 × 10−17) and ADH1C in AAs (Thr151Thr, P = 4.94 × 10−10), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P = 2.63 × 10−11), PDLIM5 in EAs (P = 2.01 × 10−8), and METAP in AAs (P = 3.35 × 10−8). We also identified a novel GWS association (1.17 × 10−10) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.

This study examined the association between two specific polymorphisms of the gene encoding the m-opioid receptor and treatment outcomes in alcohol-dependent patients who were prescribed naltrexone or placebo. A total of 82 patients (71 of European descent) who were randomized to naltrexone and 59 who were randomized to placebo (all of European descent) in one of three randomized, placebo-controlled clinical trials of naltrexone were genotyped at the A +118 G (Asn40Asp) and C +17 T (Ala6Val) SNPs in the gene encoding the m-opioid receptor (OPRM1). The association between genotype and drinking outcomes was measured over 12 weeks of treatment. In subjects of European descent, individuals with one or two copies of the Asp40 allele treated with naltrexone had significantly lower rates of relapse (p ¼ 0.044) and a longer time to return to heavy drinking (p ¼ 0.040) than those homozygous for the Asn40 allele. There were no differences in overall abstinence rates (p ¼ 0.611), nor were there differences in relapse rates or abstinence rates between the two genotype groups among those assigned to placebo. These preliminary results are consistent with prior literature demonstrating that the opioid system is involved in the reinforcing properties of alcohol and that allelic variation at OPRM1 is associated with differential response to a m-receptor antagonist. If replicated, these results would help to identify alcohol-dependent individuals who may be most likely to respond to treatment with naltrexone.

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10−35 and <10−8 respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10−6). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10−20) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.