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A polygenic p factor for major psychiatric disorders.

ABSTRACT: It has recently been proposed that a single dimension, called the p factor, can capture a person's liability to mental disorder. Relevant to the p hypothesis, recent genetic research has found surprisingly high genetic correlations between pairs of psychiatric disorders. Here, for the first time, we compare genetic correlations from different methods and examine their support for a genetic p factor. We tested the hypothesis of a genetic p factor by applying principal component analysis to matrices of genetic correlations between major psychiatric disorders estimated by three methods-family study, genome-wide complex trait analysis, and linkage-disequilibrium score regression-and on a matrix of polygenic score correlations constructed for each individual in a UK-representative sample of 7 026 unrelated individuals. All disorders loaded positively on a first unrotated principal component, which accounted for 57, 43, 35, and 22% of the variance respectively for the four methods. Our results showed that all four methods provided strong support for a genetic p factor that represents the pinnacle of the hierarchical genetic architecture of psychopathology.

SUBMITTER: Selzam S

PROVIDER: S-EPMC6168558 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A polygenic p factor for major psychiatric disorders.

Selzam Saskia S Coleman Jonathan R I JRI Caspi Avshalom A Moffitt Terrie E TE Plomin Robert R

Translational psychiatry 20181002 1

It has recently been proposed that a single dimension, called the p factor, can capture a person's liability to mental disorder. Relevant to the p hypothesis, recent genetic research has found surprisingly high genetic correlations between pairs of psychiatric disorders. Here, for the first time, we compare genetic correlations from different methods and examine their support for a genetic p factor. We tested the hypothesis of a genetic p factor by applying principal component analysis to matric ...[more]

PMID: 30279410

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Project description:ObjectiveMore than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.MethodsThe samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.ResultsThree genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).ConclusionsThis study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

Project description:Over the past decade, large-scale genetic studies have successfully identified hundreds of genetic variants robustly associated with risk for psychiatric disorders. However, mechanistic insight and clinical translation continue to lag the pace of risk variant identification, hindered by the sheer number of targets and their predominant noncoding localization, as well as pervasive pleiotropy and incomplete penetrance. Successful next steps require identification of "causal" genetic variants and their proximal biological consequences; placing variants within biologically defined functional contexts, reflecting specific molecular pathways, cell types, circuits, and developmental windows; and characterizing the downstream, convergent neurobiological impact of polygenicity within an individual. Here, we discuss opportunities and challenges of high-throughput transcriptomic profiling in the human brain, and how transcriptomic approaches can help pinpoint mechanisms underlying genetic risk for psychiatric disorders at a scale necessary to tackle daunting levels of polygenicity. These include transcriptome-wide association studies for risk gene prioritization through integration of genome-wide association studies with expression quantitative trait loci. We outline transcriptomic results that inform our understanding of the brain-level molecular pathology of psychiatric disorders, including autism spectrum disorder, bipolar disorder, major depressive disorder, and schizophrenia. Finally, we discuss systems-level approaches for integration of distinct genetic, genomic, and phenotypic levels, including combining spatially resolved gene expression and human neuroimaging maps. Results highlight the importance of understanding gene expression (dys)regulation across human brain development as a major contributor to psychiatric disease pathogenesis, from common variants acting as expression quantitative trait loci to rare variants enriched for gene expression regulatory pathways.

Project description:Many psychiatric disorders are associated with impaired executive functioning (EF). The associated EF component varies by psychiatric disorders, and this variation might be due to genetic liability. We explored the genetic association between five psychiatric disorders and EF in clinically-recruited attention deficit hyperactivity disorder (ADHD) children using polygenic risk score (PRS) methodology. Genome-wide association study (GWAS) summary data for ADHD, major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BIP) and autism were used to calculate the PRSs. EF was evaluated by the Stroop test for inhibitory control, the trail-making test for cognitive flexibility, and the digital span test for working memory in a Chinese ADHD cohort (n?=?1147). Exploratory factor analysis of the three measures identified one principal component for EF (EF-PC). Linear regression models were used to analyze the association between each PRS and the EF measures. The role of EF measures in mediating the effects of the PRSs on ADHD symptoms was also analyzed. The result showed the PRSs for MDD, ADHD and BIP were all significantly associated with the EF-PC. For each EF component, the association results were different for the PRSs of the five psychiatric disorders: the PRSs for ADHD and MDD were associated with inhibitory control (adjusted P?=?0.0183 and 0.0313, respectively), the PRS for BIP was associated with working memory (adjusted P?=?0.0416), and the PRS for SZ was associated with cognitive flexibility (adjusted P?=?0.0335). All three EF measures were significantly correlated with ADHD symptoms. In mediation analyses, the ADHD and MDD PRSs, which were associated with inhibitory control, had significant indirect effects on ADHD symptoms through the mediation of inhibitory control. These findings indicate that the polygenic risks for several psychiatric disorders influence specific executive dysfunction in children with ADHD. The results helped to clarify the relationship between risk genes of each mental disorder and the intermediate cognitive domain, which may further help elucidate the risk genes and motivate efforts to develop EF measures as a diagnostic marker and future treatment target.

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A polygenic p factor for major psychiatric disorders.

Publications

A polygenic p factor for major psychiatric disorders.

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