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Gene expression elucidates functional impact of polygenic risk for schizophrenia.

ABSTRACT: Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ?20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ? 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.

SUBMITTER: Fromer M

PROVIDER: S-EPMC5083142 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Gene expression elucidates functional impact of polygenic risk for schizophrenia.

Fromer Menachem M Roussos Panos P Sieberts Solveig K SK Johnson Jessica S JS Kavanagh David H DH Perumal Thanneer M TM Ruderfer Douglas M DM Oh Edwin C EC Topol Aaron A Shah Hardik R HR Klei Lambertus L LL Kramer Robin R Pinto Dalila D Gümüş Zeynep H ZH Cicek A Ercument AE Dang Kristen K KK Browne Andrew A Lu Cong C Xie Lu L Readhead Ben B Stahl Eli A EA Xiao Jianqiu J Parvizi Mahsa M Hamamsy Tymor T Fullard John F JF Wang Ying-Chih YC Mahajan Milind C MC Derry Jonathan M J JM Dudley Joel T JT Hemby Scott E SE Logsdon Benjamin A BA Talbot Konrad K Raj Towfique T Bennett David A DA De Jager Philip L PL Zhu Jun J Zhang Bin B Sullivan Patrick F PF Chess Andrew A Purcell Shaun M SM Shinobu Leslie A LA Mangravite Lara M LM Toyoshiba Hiroyoshi H Gur Raquel E RE Hahn Chang-Gyu CG Lewis David A DA Haroutunian Vahram V Peters Mette A MA Lipska Barbara K BK Buxbaum Joseph D JD Schadt Eric E EE Hirai Keisuke K Roeder Kathryn K Brennand Kristen J KJ Katsanis Nicholas N Domenici Enrico E Devlin Bernie B Sklar Pamela P

Nature neuroscience 20160926 11

Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was invol ...[more]

PMID: 27668389

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Project description:The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.

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Gene expression elucidates functional impact of polygenic risk for schizophrenia.

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Gene expression elucidates functional impact of polygenic risk for schizophrenia.

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