Phenome-wide analysis of genome-wide polygenic scores
Abstract
Genome-wide polygenic scores (GPS), which aggregate the effects of thousands of DNA variants from genome-wide association studies (GWAS), have the potential to make genetic predictions for individuals. We conducted a systematic investigation of associations between GPS and many behavioral traits, the behavioral phenome. For 3152 unrelated 16-year-old individuals representative of the United Kingdom, we created 13 GPS from the largest GWAS for psychiatric disorders (for example, schizophrenia, depression and dementia) and cognitive traits (for example, intelligence, educational attainment and intracranial volume). The behavioral phenome included 50 traits from the domains of psychopathology, personality, cognitive abilities and educational achievement. We examined phenome-wide profiles of associations for the entire distribution of each GPS and for the extremes of the GPS distributions. The cognitive GPS yielded stronger predictive power than the psychiatric GPS in our UK-representative sample of adolescents. For example, education GPS explained variation in adolescents' behavior problems (~0.6%) and in educational achievement (~2%) but psychiatric GPS were associated with neither. Despite the modest effect sizes of current GPS, quantile analyses illustrate the ability to stratify individuals by GPS and opportunities for research. For example, the highest and lowest septiles for the education GPS yielded a 0.5 s.d. difference in mean math grade and a 0.25 s.d. difference in mean behavior problems. We discuss the usefulness and limitations of GPS based on adult GWAS to predict genetic propensities earlier in development.Molecular Psychiatry advance online publication, 25 August 2015; doi:10.1038/mp.2015.126.
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Available from: Eva Krapohl, Aug 27, 2015
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- "Complementing prior observations from latent genetic (e.g., Kendler et al., 2003) and candidate gene (e.g., Yoshimasu et al., 2015) studies, we report that PRS derived from the PGC cross-disorder meta-analysis (CROSS; Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013) explained roughly 1% of the variance in general substance involvement (GENSUB) in our target sample enriched for substance use (SAGE; ). This effect size is consistent with previously published cross-trait PRS analyses (e.g., Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013; Krapohl et al., 2015), and, though not large enough to be informative on an individual level, nonetheless provides support for the hypothesized role of shared genetics in the lifetime co-occurrence of psychiatric and substance use disorders. PRS for individual psychiatric diagnoses (i.e., ADHD, BIP, MDD, and SCZ, but not AUT) were also significantly associated with specific substance involvement (i.e., alcohol, cannabis, cocaine, nicotine, and opioids), and are discussed in detail below. "
[Show abstract] [Hide abstract] ABSTRACT: Despite evidence of substantial comorbidity between psychiatric disorders and substance involvement, the extent to which common genetic factors contribute to their co-occurrence remains understudied. In the current study, we tested for associations between polygenic risk for psychiatric disorders and substance involvement (i.e., ranging from ever-use to severe dependence) among 2573 non-Hispanic European–American participants from the Study of Addiction: Genetics and Environment. Polygenic risk scores (PRS) for cross-disorder psychopathology (CROSS) were generated based on the Psychiatric Genomics Consortium’s Cross-Disorder meta-analysis and then tested for associations with a factor representing general liability to alcohol, cannabis, cocaine, nicotine, and opioid involvement (GENSUB). Follow-up analyses evaluated specific associations between each of the five psychiatric disorders which comprised CROSS—attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (AUT), bipolar disorder (BIP), major depressive disorder (MDD), and schizophrenia (SCZ)—and involvement with each component substance included in GENSUB. CROSS PRS explained 1.10% of variance in GENSUB in our sample (p < 0.001). After correction for multiple testing in our follow-up analyses of polygenic risk for each individual disorder predicting involvement with each component substance, associations remained between: (A) MDD PRS and non-problem cannabis use, (B) MDD PRS and severe cocaine dependence, (C) SCZ PRS and non-problem cannabis use and severe cannabis dependence, and (D) SCZ PRS and severe cocaine dependence. These results suggest that shared covariance from common genetic variation contributes to psychiatric and substance involvement comorbidity.- "These methods have the potential to identify novel and unexpected variants associated with treatment response . In conjunction with statistical approaches such as polygenic risk scoring, genome wide approaches allow the opportunity to move beyond single variant approaches to methods which aggregate across a large number of markers in order to capture a greater and ultimately clinically significant proportion of the variance in outcome [Krapohl et al., 2015; Keers et al., 2016]. An interesting avenue for further research is to investigate epigenetic and gene expression predictors and correlates of psychological treatment response, as these approaches may allow us to get closer to the biological mechanisms of CBT response. "
[Show abstract] [Hide abstract] ABSTRACT: Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re-emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre- and post-treatment and during the follow-up period in the full sample and a subset with fear-based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow-up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear-based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.- [Show abstract] [Hide abstract] ABSTRACT: In the context of current concerns about replication in psychological science, we describe 10 findings from behavioral genetic research that have replicated robustly. These are “big” findings, both in terms of effect size and potential impact on psychological science, such as linearly increasing heritability of intelligence from infancy (20%) through adulthood (60%). Four of our top 10 findings involve the environment, discoveries that could have been found only with genetically sensitive research designs. We also consider reasons specific to behavioral genetics that might explain why these findings replicate.
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