Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students.

Background: Genetic factors impact alcohol use behaviors and these factors may become increasingly evident during emerging adulthood. Examination of the effects of individual variants as well as aggregate genetic variation can clarify mechanisms underlying risk. Methods: We conducted genome-wide association studies (GWAS) in an ethnically diverse sample of college students for three quantitative outcomes including typical monthly alcohol consumption, alcohol problems, and maximum number of drinks in 24 h. Heritability based on common genetic variants (h2SNP) was assessed. We also evaluated whether risk variants in aggregate were associated with alcohol use outcomes in an independent sample of young adults. Results: Two genome-wide significant markers were observed: rs11201929 in GRID1 for maximum drinks in 24 h, with supportive evidence across all ancestry groups; and rs73317305 in SAMD12 (alcohol problems), tested only in the African ancestry group. The h2SNP estimate was 0.19 (SE = 0.11) for consumption, and was non-significant for other outcomes. Genome-wide polygenic scores were significantly associated with alcohol outcomes in an independent sample. Conclusions: These results robustly identify genetic risk for alcohol use outcomes at the variant level and in aggregate. We confirm prior evidence that genetic variation in GRID1 impacts alcohol use, and identify novel loci of interest for multiple alcohol outcomes in emerging adults. These findings indicate that genetic variation influencing normative and problematic alcohol use is, to some extent, convergent across ancestry groups. Studying college populations represents a promising avenue by which to obtain large, diverse samples for gene identification.

Dimensionality and Genetic Correlates of Problem Behavior in Low-Income African American Adolescents.

Researchers have long observed that problem behaviors tend to cluster together, particularly among adolescents. Epidemiological studies have suggested that this covariation is due, in part, to common genetic influences, and a number of plausible candidates have emerged as targets for investigation. To date, however, genetic association studies of these behaviors have focused mostly on unidimensional models of individual phenotypes within European American samples. Herein, we compared a series of confirmatory factor models to best characterize the structure of problem behavior (alcohol and marijuana use, sexual behavior, and disruptive behavior) within a representative community-based sample of 592 low-income African American adolescents (50.3% female), ages 13 to 18. We further explored the extent to which 3 genes previously implicated for their role in similar behavioral dimensions (CHRM2, GABRA2, and OPRM1) independently accounted for variance within factors specified in the best-fitting model. Supplementary analyses were conducted to derive comparative estimates for the predictive utility of these genes in more traditional unidimensional models. Findings provide initial evidence for a bifactor structure of problem behavior among African American adolescents and highlight novel genetic correlates of specific behavioral dimensions otherwise undetected in an orthogonal syndromal factor. Implications of this approach include increased precision in the assessment of problem behavior, with corresponding increases in the reliability and validity of identified genetic associations. As a corollary, the comparison of primary and supplementary association analyses illustrates the potential for overlooking and/or overinterpreting meaningful genetic effects when failing to adequately account for phenotypic complexity.

Can Genetics Predict Response to Complex Behavioral Interventions? Evidence from a Genetic Analysis of the Fast Track Randomized Control Trial.

Early interventions are a preferred method for addressing behavioral problems in high-risk children, but often have only modest effects. Identifying sources of variation in intervention effects can suggest means to improve efficiency. One potential source of such variation is the genome. We conducted a genetic analysis of the Fast Track randomized control trial, a 10-year-long intervention to prevent high-risk kindergarteners from developing adult externalizing problems including substance abuse and antisocial behavior. We tested whether variants of the glucocorticoid receptor gene NR3C1 were associated with differences in response to the Fast Track intervention. We found that in European-American children, a variant of NR3C1 identified by the single-nucleotide polymorphism rs10482672 was associated with increased risk for externalizing psychopathology in control group children and decreased risk for externalizing psychopathology in intervention group children. Variation in NR3C1 measured in this study was not associated with differential intervention response in African-American children. We discuss implications for efforts to prevent externalizing problems in high-risk children and for public policy in the genomic era.

Effect of OPRM1 and stressful life events on symptoms of major depression in African American adolescents.

BACKGROUND: In a community sample of low-income African American adolescents, we tested the interactive effects of variation in the mu 1 opioid receptor (OPRM1) gene and the occurrence of stressful life events on symptoms of depression. METHOD: Interactive effects of 24 OPRM1 simple nucleotide polymorphisms (SNP) and adolescent report of stressful life events on depression were tested using multilevel regressions. SNPs were dummy coded to test both additive and dominate forms of coding. RESULTS: Five OPRM1 SNPs showed significant evidence of interaction with stressful life events to alter depression risk (or symptoms) after adjusting for multiple testing and the correlated nature of the SNPs. Follow-up analyses showed significant differences based on OPRM1 genotype at both lower and higher frequencies of stressful life events, suggesting that participants with a copy of the minor allele on OPRM1 SNPs rs524731, rs9478503, rs3778157, rs10485057, and rs511420 have fewer symptoms in low stress conditions but more symptoms in high stress conditions compared to major allele homozygotes. LIMITATIONS: The genetic variants associated with depression in African American adolescents may not translate to other ethnic groups. This study is also limited in that only one gene that functions within a complex biological system is addressed. CONCLUSIONS: This current study is the first to find an interaction between OPRM1 and life stress that is associated with depression. It also addressed an understudied population within the behavioral genetics literature. Further research should test additional genes involved in the opioid system and expand the current findings to more diverse samples.

Spit for Science: launching a longitudinal study of genetic and environmental influences on substance use and emotional health at a large US university.

Finding genes involved in complex behavioral outcomes, and understanding the pathways by which they confer risk, is a challenging task, necessitating large samples that are phenotypically well characterized across time. We describe an effort to create a university-wide research project aimed at understanding how genes and environments impact alcohol use and related substance use and mental health outcomes across time in college students. Nearly 70% of the incoming freshman class (N = 2715) completed on-line surveys, with 80% of the students from the fall completing spring follow-ups. 98% of eligible participants also gave DNA. The participants closely approximated the university population in terms of gender and racial/ethnic composition. Here we provide initial results on alcohol use outcomes from the first wave of the sample, as well as associated predictor variables. We discuss the potential for this kind of research to advance our understanding of genetic and environment influences on substance use and mental health outcomes.

Prioritization and association analysis of murine-derived candidate genes in anxiety-spectrum disorders.

BACKGROUND: Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions. METHODS: We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression). RESULTS: Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing. CONCLUSIONS: Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.

Association study between GABA receptor genes and anxiety spectrum disorders.

BACKGROUND: Human anxiety disorders are complex diseases with relatively unknown etiology. Dysfunction of the Gamma-aminobutyric acid (GABA) system has been implicated in many neuropsychiatric conditions, including anxiety and depressive disorders. In this investigation, we explored four GABA receptor genes for their possible associations with genetic risk for anxiety disorders and depression. METHODS: Our study sample consisted of 589 cases and 539 controls selected from a large population-based twin registry based upon a latent genetic risk factor shared by several anxiety disorders, major depression, and neuroticism. We subjected these to a two-stage protocol, in which all candidate genetic markers were screened for association in stage 1 (N=376), the positive results of which were tested for replication in stage 2 (N=752). We analyzed data from 26 single nucleotide polymorphisms (SNPs) from four GABA receptor genes: GABRA2, GABRA3, GABRA6, and GABRG2. RESULTS: Of the 26 SNPs genotyped in stage 1, we identified two markers in GABRA3 that met the threshold (P < or = .1) to be tested in stage 2. Phenotypic associations of these two markers failed to replicate in stage 2. CONCLUSIONS: These findings suggest that common variation in the GABRA2, GABRA3, GABRA6, and GABRG2 genes does not play a major role in liability to anxiety spectrum disorders.

Apoptotic engulfment pathway and schizophrenia.

BACKGROUND: Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease. METHODOLOGY/PRINCIPAL FINDINGS: Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples. CONCLUSIONS/SIGNIFICANCE: From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease.

FBXL21 association with schizophrenia in Irish family and case-control samples.

FBXL21 gene encodes an F-box containing protein functioning in the SCF ubiquitin ligase complex. The role of the F-box protein is to recruit proteins designated for degradation to the ligase complex so they would be ubiquitinated. Using both family and case-control samples, we found consistent associations in and around FBXL21 gene. In the family sample (Irish study of high density schizophrenia families, ISHDSF, 1,350 subjects from 273 families), a minimal PDT P-value of 0.0011 was observed at rs31555. In the case-control sample (Irish case-control study of schizophrenia, ICCSS, 814 cases and 625 controls), significant associations were observed at two markers (rs1859427 P = 0.0197, and rs6861170 P = 0.0197). In haplotype analyses, haplotype 1-1 (C-T) of rs1859427-rs6861170 was overtransmitted in the ISHDSF (P = 0.0437) and was overrepresented in the ICCSS (P = 0.0177). For both samples, the associated alleles and haplotypes were identical. These data suggested that FBXL21 may be associated with schizophrenia in the Irish samples.

Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women.

Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p = 2.9 x 10(-5) in women), with a significant gene-sex effect (p = 1.8 x 10(-4)). We studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p = 2.1 x 10(-3) in women; p = 4.2 x 10(-3) for gene-sex interaction). Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p = 8.8 x 10(-7); p = 1.6 x 10(-5) for gene-sex interaction). The female-specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease.