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Phenotypically independent mental health symptom profiles are genetically related

By Daniel Roelfs, Dag Aln├Žs, Oleksandr Frei, Dennis van der Meer, Olav B Smeland, Ole Andreassen, Lars T. Westlye, Tobias Kaufmann

Posted 30 Mar 2020
medRxiv DOI: 10.1101/2020.03.30.20045591

ImportanceGenome-wide association studies (GWAS) and family-based studies have revealed partly overlapping genetic architectures between various psychiatric disorders. Given clinical overlap between disorders our knowledge of the genetic architectures underlying specific symptom profiles is limited, and the predominant use of classical case-control designs have not allowed the study of variations in mental health independent of diagnosis. ObjectiveTo derive distinct profiles of mental symptoms in healthy individuals and to study how these genetically relate to each other and to common psychiatric disorders. DesignThis is a cross-sectional study using self-report mental health questionnaires and molecular genetic data. SettingWe used population-based data from the UK Biobank. ParticipantsData from individuals with a diagnosed neurological or psychiatric disorder were excluded, allowing us to study variations in mental health in 139,006 healthy individuals, and genotypes in 117,088 healthy individuals with Caucasian ancestry. Main Outcomes and MeasuresWe decomposed self-report mental health questionnaires into twelve distinct symptom profiles using independent component analysis, and performed a GWAS for each of them. Using GWAS summary statistics, we assessed genetic correlations between the symptom profiles, and between symptom profiles and common psychiatric disorders and cognitive traits. ResultsWe found that symptom profiles were genetically correlated with a wide range of psychiatric disorders and cognitive traits (67 out of 108 correlations significant at p < FDR), with strongest effects typically observed between a given symptom profile and a disorder for which the symptom is common (e.g. depression symptoms and major depressive disorder, trauma experience and post-traumatic stress disorder). Strikingly, although the symptom profiles were phenotypically uncorrelated, many of them were genetically correlated with each other (31 out of 66 comparisons significant; p < FDR). Conclusions and RelevanceThis study provides evidence that statistically independent mental health profiles in healthy individuals partly share genetic underpinnings and show genetic overlaps with psychiatric disorders. These findings suggest that shared genetics across psychiatric disorders cannot be exclusively attributed to the overlapping symptomatology between and the heterogeneity within psychiatric disorders, and supports that moving from a classical case-control setting to a continuous mental health spectrum may complement the study of psychiatric genetics. Key pointsO_ST_ABSQuestionC_ST_ABSHow to statistically independent mental health profiles genetically correlate with each other, and with psychiatric disorders and cognitive traits? FindingsSymptom profiles capturing different facets of mental health that were phenotypically uncorrelated were nonetheless genetically correlated. The symptom profiles also genetically correlated with psychiatric disorders and cognitive traits and although strongest correlations were typically observed between a given symptom profile and a disorder for which the symptom is common, specificity was overall limited. MeaningThe genetic correlations of phenotypically independent symptom profiles may suggest that the known pleiotropy among common psychiatric disorders cannot be exclusively attributed to the overlapping symptomatology between the disorders.

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