Multi-tissue transcriptome analyses identify genetic mechanisms underlying neuropsychiatric traits

• Published in: Nature genetics Vol. 51; no. 6; pp. 933 - 940
• Main Authors: Gamazon, Eric R., Zwinderman, Aeilko H., Cox, Nancy J., Denys, Damiaan, Derks, Eske M.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2019; Nature Publishing Group
• Subjects: 38; 38/91; 45; 45/23; 45/43; 631/208/199; 631/208/212; 631/208/212/2019; 692/699/476/1799; Adrenal glands; Agriculture; Algorithms; Animal Genetics and Genomics; Attention deficit hyperactivity disorder; Biomedical and Life Sciences; Biomedicine; Bipolar disorder; Blood pressure; Brain; Brain mapping; Cancer Research; Colon; Computational Biology - methods; Consortia; Diagnosis; Disorders; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene Function; Gene mapping; Gene Regulatory Networks; Genes; Genetic analysis; Genetic aspects; Genetic Association Studies - methods; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomes; Health risks; Heterogeneity; Human Genetics; Humans; Letter; Mapping; Mental depression; Mental disorders; Mental Disorders - diagnosis; Mental Disorders - genetics; Mental Disorders - psychology; Mental illness; Nervous system diseases; Non-coding RNA; Organ Specificity; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Quantitative Trait, Heritable; Schizophrenia; Studies; Tissue analysis; Tissues; Transcriptome; Uniqueness; United Kingdom > UK
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-019-0409-8

The genetic architecture of psychiatric disorders is characterized by a large number of small-effect variants 1 located primarily in non-coding regions, suggesting that the underlying causal effects may influence disease risk by modulating gene expression 2 – 4 . We provide comprehensive analyses using transcriptome data from an unprecedented collection of tissues to gain pathophysiological insights into the role of the brain, neuroendocrine factors (adrenal gland) and gastrointestinal systems (colon) in psychiatric disorders. In each tissue, we perform PrediXcan analysis and identify trait-associated genes for schizophrenia ( n associations = 499; n unique genes = 275), bipolar disorder ( n associations = 17; n unique genes = 13), attention deficit hyperactivity disorder ( n associations = 19; n unique genes = 12) and broad depression ( n associations = 41; n unique genes = 31). Importantly, both PrediXcan and summary-data-based Mendelian randomization/heterogeneity in dependent instruments analyses suggest potentially causal genes in non-brain tissues, showing the utility of these tissues for mapping psychiatric disease genetic predisposition. Our analyses further highlight the importance of joint tissue approaches as 76% of the genes were detected only in difficult-to-acquire tissues. Multi-tissue transcriptome analyses using PrediXcan identify numerous trait-associated genes for schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and broad depression, and highlight potentially causal genes in non-brain tissues.