A cross-disorder MR-pheWAS of 5 major psychiatric disorders in UK Biobank
Authors: Leppert Beate , Millard Louise AC , Riglin Lucy , Smith George Davey , Thapar Anita , Tilling Kate , Walton Esther , Stergiakouli Evie 
Published: May 2019

ABSTRACTPsychiatric 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 300,000 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<2.55×10−06) for associations of PRSs with 226 outcomes, most of them attributed to associations of PRSMDD(n=120) with mental health factors and PRSADHD(n=77) with socio-demographic factors. Among others, we found strong evidence of associations between a 1 standard deviation increase in PRSADHDwith 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]: −1.26,−0.94]; PRSASDwith 0.01% reduced lower erythrocyte distribution width [95%CI: −0.013,-0.007]; PRSSCZwith 0.98 odds of playing computer games [95%CI:0.976,0.989]; PRSMDDwith a 0.11 points higher neuroticism score [95%CI:0.094,0.118] and PRSBPwith 1.04 higher odds of having a university degree [95%CI:1.033,1.048].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.AUTHOR SUMMARYPsychiatric disorders are associated with a wide range of adverse health, social and economic problems. Our study investigates the association of genetic risk for five common psychiatric disorders with socio-demographics, lifestyle and health of about 330,000 participants in the UK Biobank using a systematic, hypothesis-free approach. We found that genetic risk for attention deficit/hyperactivity disorder (ADHD) and bipolar disorder were most strongly associated with lifestyle factors, such as time of first sexual intercourse and educational attainment. Genetic risks for autism spectrum disorder and schizophrenia were associated with altered blood cell counts and time playing computer games, respectively. Increased genetic risk for depression was associated with other mental health outcomes such as neuroticism and irritability. In general, our results suggest that genetic risk for psychiatric disorders associates with a range of health and lifestyle traits that were measured in adulthood, in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis. However, it is important to note that these associations aren’t necessary causal but can themselves be influenced by other factors, like socio-economic factors and selection into the cohort. The findings inform future hypotheses to be tested using causally informative designs.