Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Abstract

Highlights d Three groups of highly genetically-related disorders among 8 psychiatric disorders d Identified 109 pleiotropic loci affecting more than one disorder d Pleiotropic genes show heightened expression beginning in 2 nd prenatal trimester d Pleiotropic genes play prominent roles in neurodevelopmental processes Authors Cross-Disorder Group of the Psychiatric Genomics Consortium

Investigating regions of shared genetic variation in attention deficit/hyperactivity disorder and major depressive disorder: A GWAS meta-analysis

“…The region that includes rs12658032 is associated with multiple traits and therefore warrants further interrogation. A recent study reported a SNP in this region (rs1363105, a SNP in LD with rs12658032) that was associated with ADHD, MDD, ASD and anorexia (35).…”

Testing structural models of psychopathology at the genomic level

“…Their results indicated that each disorder had a moderate-to-high loading on the common factor, revealing that genetic covariation among psychiatric disorders can be captured using factor analysis. Lee et al 20 used an exploratory approach to examine the genetic covariance among eight psychiatric disorders using GWAS summary statistics, and found evidence for a three-factor model which included factors representing compulsive behaviors, mood and psychotic disorders, and neurodevelopmental disorders.…”

“…In the present study, we capitalized on the fourteen largest GWAS of psychiatric disorders and related psychological traits to obtain estimates of genetic correlations and test alternative structural models of psychopathology at the genomic level. We included more disorders and traits and tested more alternative models of psychopathology than in previous studies 19,20 , guided by both the phenotypic literature and previously estimated genetic correlations. We also evaluated the construct validity of our best-fitting model by estimating genetic correlations between the higher-order factors and external criterion variables, such as educational attainment and personality characteristics.…”

Genetic correlates of socio-economic status influence the pattern of shared heritability across mental health traits

“…This has consequences for conceptualizations of an underlying psychopathology factor (i.e., p-factor). 2,29,48 While the strength of genetic association within the substance use cluster decreased on average after partialling out SES, the average strength of genetic association within the two psychiatric disorder clusters did not change substantially. However, the effect of partialling out SES had strong effects on some genetic associations within the psychiatric clusters (either becoming stronger or weaker) but not on others (also see Figure 4).…”

“…Previous studies reported robust evidence of high comorbidity between different mental health disorders, indicating that individuals with a diagnosis of one disorder are more likely to develop other mental health problems. Genetic studies may provide useful information on the contribution of shared genetic risk factors to the observed comorbidities, and thus potentially gives insights into shared underlying biology and pathology 1,2 . However, possible confounders such as socio-economic status (SES) may be correlated with genetic variation 3 and should therefore be appropriately accounted for.…”