A cross-disorder PRS-pheWAS of 5 major psychiatric disorders in UK Biobank

Abstract

Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 330,000 participants from the UK Biobank to examine associations of polygenic risk scores (PRS) for five psychiatric disorders (major depression (MDD), bipolar disorder (BP), schizophrenia (SCZ), attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) with 23,004 outcomes in UK Biobank, using the open-source PHESANT software package. There was evidence after multiple testing (p<2.55x10-06) for associations of PRSs with 294 outcomes, most of them attributed to associations of PRS MDD (n = 167) and PRS SCZ (n = 157) with mental health factors. Among others, we found strong evidence of association of higher PRS ADHD with 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]:-1.25,-0.92] and a history of physical maltreatment; PRS ASD with 0.01% lower erythrocyte distribution width [95%CI:-0.013,-0.007]; PRS SCZ with 0.95 lower odds of playing computer games [95%CI:0.95,0.96]; PRS MDD with a 0.12 points higher neuroticism score [95%CI:0.111,0.135] and PRS BP with 1.03 higher odds of having a university degree [95%CI:1.02,1.03]. We were able to show that genetic liabilities for five major psychiatric disorders associate with long-term aspects of adult life, including socio-demographic factors, mental and physical health. This is evident even in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis.

Mapping relationships between ADHD genetic liability, stressful life events, and ADHD symptoms in healthy adults

“…Associations with measures of SLEs were seen with several of the disorders. These results are in line with a previous study reporting that the PRSs for five major psychiatric disorders are associated with mental health‐related traits in adult life in the general population; more specifically, the PRSs for ADHD, MDD, and SCZ have been found associated with trauma‐related phenotypes (Leppert et al, 2020 ). MDD was the only disorder, which was related both to ADHD symptoms and to SLEs.…”

The Effect of Attention Deficit/Hyperactivity Disorder on Physical Health Outcomes: A 2-Sample Mendelian Randomization Study

“…ADHD symptoms tend to persist into adulthood in 65% of children diagnosed with the condition ( 3 ). Even when ADHD symptoms do not persist into adulthood, childhood ADHD symptoms can potentially have long-lasting effects on physical health later in life ( 51 ).…”

A Phenome-Wide Association Study (PheWAS) of COVID-19 Outcomes by Race Using the Electronic Health Records Data in Michigan Medicine

“…PheWAS typically associates a genetic variant ( ) with hundreds of disease codes ( ) with association models of the structure . Due to computational advances and development of widely available analytic frameworks [ 2 , 3 , 4 , 5 , 6 ], PheWAS is now relatively easy to implement. The main goal of a PheWAS is to replicate known gene–disease relationships and to search for hidden and unanticipated associations (for example, Li et al found that there is a strong negative association between the tag single nucleotide polymorphism (SNP) for blood group O antigen and arm impedance) [ 2 , 7 , 8 , 9 , 10 ].…”