On the genetic and environmental associations between body composition, depression symptoms and smoking behavior.

Obesity is a serious public health crisis and recent estimates of its incidence are the highest in United States history, with 35% and 17% of American adults and children affected, respectively. The clinical definition of adult obesity is operationalized as a body mass index (BMI) greater than 30 kg/m2. Although the prevalence of common obesity has increased dramatically over the past 30 years–largely thought to be due to changes in the environment, such as high calorie diets and sedentary lifestyles—twin and family studies have shown consistently that relative body weight is under considerable genetic influence in both children and adults, with heritability estimates ranging from 40% to 90%. Elucidating the genetic and environmental liability to relative body weight is an important public health endeavor. To further our understanding of the genetics of BMI and common complex obesity, several studies are described that integrate clinical, twin, and genome-wide association (GWAS) methodology in the context of genetic risk scores, clinical risk prediction, development across adolescence into adulthood, and comorbidity with depression symptoms and smoking behavior. First, in two cross-sectional genetic association studies, the utility of genetic risk sum scores (GRSS) were assessed, which summarize the total number of risk alleles, as an alternative form of replication and for potential clinical utility for obesity risk prediction. Next, since there has been only limited research on when during development BMI-associated variants begin influencing BMI, a longitudinal twin study was utilized to assess the effects of adult-validated BMI-SNPs across adolescence into adulthood. In addition, obesity is comorbid with numerous medical conditions including cardiovascular disease, insulin-resistance and some forms of cancer, as well as, various psychiatric disorders including eating disorders, mood disorders, and substance use. The next series of studies aimed to understand phenotypic and genetic associations between BMI/obesity and binge eating disorder (BED), depression symptoms and smoking behavior. Using a clinical sample of overweight and obese women with and without BED, the relationship of BED, food intake and internalizing symptoms of depression and anxiety was examined. Next, twin study methodology was used to investigate if shared genetic and/or environmental liability was responsible for phenotypic associations found between BMI, depression symptoms, and impulsivity. Finally, a genetic association study aimed at investigating whether genetic variants were associated with multiple behaviors, body composition and smoking behavior, or were trait-specific is presented. By utilizing several samples and methodologies and by pursuing methods development, a comprehensive approach is presented that is hoped to represent a more powerful evidence-based strategy to understanding the genetic and environmental determinants of BMI and common complex obesity, along with associated depression symptoms and smoking behavior

Binge Eating Disorder Mediates Links between Symptoms of Depression and Anxiety and Caloric Intake in Obese Women

Despite considerable comorbidity between mood disorders, binge eating disorder (BED), and obesity, the underlying mechanisms remain unresolved. Therefore, the purpose of this study was to examine models by which internalizing behaviors of depression and anxiety influence food intake in overweight/obese women. Thirty-two women (15 BED, 17 controls) participated in a laboratory eating-episode and completed questionnaires assessing symptoms of anxiety and depression. Path analysis was used to test mediation and moderation models to determine the mechanisms by which internalizing symptoms influenced kilocalorie (kcal) intake. The BED group endorsed significantly more symptoms of depression (10.1 versus 4.8, P=0.005 ) and anxiety (8.5 versus 2.7, P=0.003). Linear regression indicated that BED diagnosis and internalizing symptoms accounted for 30% of the variance in kcal intake. Results from path analysis suggested that BED mediates the influence of internalizing symptoms on total kcal intake. The associations between internalizing symptoms and food intake are best described as operating indirectly through a BED diagnosis. This suggests that symptoms of depression and anxiety influence whether one engages in binge eating, which influences kcal intake. Greater understanding of the mechanisms underlying the associations between mood, binge eating, and food intake will facilitate the development of more effective prevention and treatment strategies for both BED and obesity

Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE.

BACKGROUND: The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets. METHODS: Using a large case-control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status. RESULTS: Over and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD. CONCLUSIONS: Results indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research

Intermediate stable states in substance use

Many people across the world use potentially addictive legal and illegal substances, but evidence suggests that not all use leads to heavy use and dependence, as some substances are used moderately for long periods of time. Here, we empirically examine, the stability of and transitions between three substance use states: zero-use, moderate use, and heavy use. We investigate two large datasets from the US and the Netherlands on yearly usage and change of alcohol, nicotine, and cannabis. Results, which we make available through an extensive interactive tool, suggests that there are stable moderate use states, even after meeting criteria for a positive diagnosis of substance abuse or dependency, for both alcohol and cannabis use. Moderate use of tobacco, however, was rare. We discuss implications of recognizing three states rather than two states as a modeling target, in which the moderate use state can both act as an intervention target or as a gateway between zero use and heavy use

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

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

On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis

Background As the architecture of complex traits incorporates a widening spectrum of genetic variation, analyses integrating common and rare variation are needed. Body mass index (BMI) represents a model trait, since common variation shows robust association but accounts for a fraction of the heritability. A combined analysis of single nucleotide polymorphisms (SNP) and copy number variation (CNV) was performed using 1850 European and 498 African-Americans from the Study of Addiction: Genetics and Environment. Genetic risk sum scores (GRSS) were constructed using 32 BMI-validated SNPs and aggregate-risk methods were compared: count versus weighted and proxy versus imputation. Results The weighted SNP-GRSS constructed from imputed probabilities of risk alleles performed best and was highly associated with BMI (p = 4.3×10−16) accounting for 3% of the phenotypic variance. In addition to BMI-validated SNPs, common and rare BMI/obesity-associated CNVs were identified from the literature. Of the 84 CNVs previously reported, only 21-kilobase deletions on 16p12.3 showed evidence for association with BMI (p = 0.003, frequency = 16.9%), with two CNVs nominally associated with class II obesity, 1p36.1 duplications (OR = 3.1, p = 0.009, frequency 1.2%) and 5q13.2 deletions (OR = 1.5, p = 0.048, frequency 7.7%). All other CNVs, individually and in aggregate, were not associated with BMI or obesity. The combined model, including covariates, SNP-GRSS, and 16p12.3 deletion accounted for 11.5% of phenotypic variance in BMI (3.2% from genetic effects). Models significantly predicted obesity classification with maximum discriminative ability for morbid-obesity (p = 3.15×10−18). Conclusion Results show that incorporating validated effect sizes and allelic probabilities improve prediction algorithms. Although rare-CNVs did not account for significant phenotypic variation, results provide a framework for integrated analyses

Concerns About the Use of Polygenic Embryo Screening for Psychiatric and Cognitive Traits

Private companies have begun offering services to allow parents undergoing in-vitro fertilisation to screen embryos for genetic risk of complex diseases, including psychiatric disorders. This procedure, called polygenic embryo screening, raises several difficult scientific and ethical issues, as discussed in this Personal View. Polygenic embryo screening depends on the statistical properties of polygenic risk scores, which are complex and not well studied in the context of this proposed clinical application. The clinical, social, and ethical implications of polygenic embryo screening have barely been discussed among relevant stakeholders. To our knowledge, the International Society of Psychiatric Genetics is the first professional biomedical organisation to issue a statement regarding polygenic embryo screening. For the reasons discussed in this Personal View, the Society urges caution and calls for additional research and oversight on the use of polygenic embryo screening

Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses

Genome-wide association study meta-analyses have robustly implicated three loci that affect susceptibility for smoking: CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6 and EGLN2\CYP2A6. Functional follow-up studies of these loci are needed to provide insight into biological mechanisms. However, these efforts have been hampered by a lack of knowledge about the specific causal variant(s) involved. In this study, we prioritized variants in terms of the likelihood they account for the reported associations. We employed targeted capture of the CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6, and EGLN2\CYP2A6 loci and flanking regions followed by next-generation deep sequencing (mean coverage 78×) to capture genomic variation in 363 individuals. We performed single locus tests to determine if any single variant accounts for the association, and examined if sets of (rare) variants that overlapped with biologically meaningful annotations account for the associations. In total, we investigated 963 variants, of which 71.1% were rare (minor allele frequency < 0.01), 6.02% were insertion/deletions, and 51.7% were catalogued in dbSNP141. The single variant results showed that no variant fully accounts for the association in any region. In the variant set results, CHRNB4 accounts for most of the signal with significant sets consisting of directly damaging variants. CHRNA6 explains most of the signal in the CHRNB3\CHRNA6 locus with significant sets indicating a regulatory role for CHRNA6. Significant sets in CYP2A6 involved directly damaging variants while the significant variant sets suggested a regulatory role for EGLN2. We found that multiple variants implicating multiple processes explain the signal. Some variants can be prioritized for functional follow-up. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: [email protected]

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings