Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while ...here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (
~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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/m 2. 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.
Identifying genetic relationships between complex traits in emerging adulthood can provide useful etiological insights into risk for psychopathology. College-age individuals are under-represented in ...genomic analyses thus far, and the majority of work has focused on the clinical disorder or cognitive abilities rather than normal-range behavioral outcomes.
This study examined a sample of emerging adults 18-22 years of age (N = 5947) to construct an atlas of polygenic risk for 33 traits predicting relevant phenotypic outcomes. Twenty-eight hypotheses were tested based on the previous literature on samples of European ancestry, and the availability of rich assessment data allowed for polygenic predictions across 55 psychological and medical phenotypes.
Polygenic risk for schizophrenia (SZ) in emerging adults predicted anxiety, depression, nicotine use, trauma, and family history of psychological disorders. Polygenic risk for neuroticism predicted anxiety, depression, phobia, panic, neuroticism, and was correlated with polygenic risk for cardiovascular disease.
These results demonstrate the extensive impact of genetic risk for SZ, neuroticism, and major depression on a range of health outcomes in early adulthood. Minimal cross-ancestry replication of these phenomic patterns of polygenic influence underscores the need for more genome-wide association studies of non-European populations.
Posttraumatic Stress Disorder (PTSD) is associated with increased alcohol use and alcohol use disorder (AUD), which are all moderately heritable. Studies suggest the genetic association between PTSD ...and alcohol use differs from that of PTSD and AUD, but further analysis is needed.
We used genomic Structural Equation Modeling (genomicSEM) to analyze summary statistics from large-scale genome-wide association studies (GWAS) of European Ancestry participants to investigate the genetic relationships between PTSD (both diagnosis and re-experiencing symptom severity) and a range of alcohol use and AUD phenotypes.
When we differentiated genetic factors for alcohol use and AUD we observed improved model fit relative to models with all alcohol-related indicators loading onto a single factor. The genetic correlations (rG) of PTSD were quite discrepant for the alcohol use and AUD factors. This was true when modeled as a three-correlated-factor model (PTSD-AUD rG:.36, p < .001; PTSD-alcohol use rG: −0.17, p < .001) and as a Bifactor model, in which the common and unique portions of alcohol phenotypes were pulled out into an AUD-specific factor (rG with PTSD:.40, p < .001), AU-specific factor (rG with PTSD: −0.57, p < .001), and a common alcohol factor (rG with PTSD:.16, NS).
These results indicate the genetic architecture of alcohol use and AUD are differentially associated with PTSD. When the portions of variance unique to alcohol use and AUD are extracted, their genetic associations with PTSD vary substantially, suggesting different genetic architectures of alcohol phenotypes in people with PTSD.
•Using genomic Structural Equation Modeling (gSEM), a Bifactor model fit best.•The genetic correlation between PTSD and AUD was significant and positive.•The genetic correlation between PTSD and alcohol use was significant and negative.•The genetic correlation between PTSD and the general alcohol factor was NS.
Alcohol misuse (AM) is highly prevalent and harmful, with theorized subgroups differing on internalizing and externalizing dimensions. Despite known heterogeneity, genome-wide association studies ...(GWAS) are usually conducted on unidimensional phenotypes. These approaches have identified important genes related to AM but fail to capture a large part of the heritability, even with recent increases in sample sizes. This study aimed to address phenotypic heterogeneity in GWAS to aid gene finding and to uncover the etiology of different types of AM. Genetic and phenotypic data from 410,414 unrelated individuals of multiple ancestry groups (primarily European) in the UK Biobank were obtained. Mixture modeling was applied to measures of alcohol misuse and internalizing/externalizing psychopathology to uncover phenotypically homogenous subclasses, which were carried forward to GWAS and functional annotation. A four-class model emerged with "low risk", "internalizing-light/non-drinkers", "heavy alcohol use-low impairment", and "broad high risk" classes. SNP heritability ranged from 3 to 18% and both known AM signals and novel signals were captured by genomic risk loci. Class comparisons showed distinct patterns of regional brain tissue enrichment and genetic correlations with internalizing and externalizing phenotypes. Despite some limitations, this study demonstrated the utility of genetic research on homogenous subclasses. Not only were novel genetic signals identified that might be used for follow-up studies, but addressing phenotypic heterogeneity allows for the discovery and investigation of differential genetic vulnerabilities in the development of AM, which is an important step towards the goal of personalized medicine.
Background and Aims
College students report high levels of alcohol use, which can be exacerbated by interpersonal trauma exposure (IPT). Romantic relationships may represent salient contexts for ...moderating associations between IPT and alcohol use. We examined whether relationship status, partner alcohol use and relationship satisfaction moderated associations between IPT and alcohol use, and whether these associations varied in a sex‐specific manner.
Design
University‐wide longitudinal survey of college students.
Setting
Large, urban public university in mid‐Atlantic United States.
Participants
We used two subsets of participants (n = 5673 and 3195) from the Spit for Science project, a longitudinal study of college students. Participants completed baseline assessments during the autumn of their freshman year and were invited to complete follow‐up assessments every spring thereafter. Participants were included in the present study if they completed surveys at baseline and at least one follow‐up assessment (meanfollow‐ups = 1.70, range = 1–4).
Measurements
Predictors included precollege and college‐onset IPT, relationship status, partner alcohol use, relationship satisfaction and sex. Alcohol consumption was the primary outcome of interest. Pre‐college IPT was measured at baseline and all other measures were assessed at each follow‐up.
Findings
Individuals with pre‐college IPT consumed more alcohol than those without IPT, but this was mitigated for those in relationships (β = −0.15, P = 0.046, 95% confidence interval (CI) = −0.29, 0.00). Individuals with college‐onset IPT consumed more alcohol than those without IPT, and this was more pronounced for those with higher partner alcohol use (β = −0.18, P = 0.001, 95% CI = −0.29, −0.07). Relationship satisfaction was not a significant moderator of the associations between IPT and alcohol use (Ps > 0.05 and 95% CIs include 0).
Conclusions
Involvement in relationships, but not relationship satisfaction, appears to reduce the effects of interpersonal trauma exposure (IPT) on alcohol use among US college students, while high partner alcohol use appears to exacerbate it. The moderating effects of relationship characteristics depend on the developmental timing of IPT.
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