PUBLICATION
Gene expression elucidates functional impact of polygenic risk for schizophrenia
- Authors
- Fromer, M., Roussos, P., Sieberts, S.K., Johnson, J.S., Kavanagh, D.H., Perumal, T.M., Ruderfer, D.M., Oh, E.C., Topol, A., Shah, H.R., Klei, L.L., Kramer, R., Pinto, D., Gümüş, Z.H., Cicek, A.E., Dang, K.K., Browne, A., Lu, C., Xie, L., Readhead, B., Stahl, E.A., Xiao, J., Parvizi, M., Hamamsy, T., Fullard, J.F., Wang, Y.C., Mahajan, M.C., Derry, J.M., Dudley, J.T., Hemby, S.E., Logsdon, B.A., Talbot, K., Raj, T., Bennett, D.A., De Jager, P.L., Zhu, J., Zhang, B., Sullivan, P.F., Chess, A., Purcell, S.M., Shinobu, L.A., Mangravite, L.M., Toyoshiba, H., Gur, R.E., Hahn, C.G., Lewis, D.A., Haroutunian, V., Peters, M.A., Lipska, B.K., Buxbaum, J.D., Schadt, E.E., Hirai, K., Roeder, K., Brennand, K.J., Katsanis, N., Domenici, E., Devlin, B., Sklar, P.
- ID
- ZDB-PUB-160927-2
- Date
- 2016
- Source
- Nature Neuroscience 19(11): 1442-1453 (Journal)
- Registered Authors
- Katsanis, Nicholas
- Keywords
- Databases, Gene expression, Genetics of the nervous system, Genomics, Schizophrenia
- MeSH Terms
-
- Brain/metabolism
- Female
- Gene Expression Regulation/genetics*
- Genetic Predisposition to Disease*
- Genome-Wide Association Study
- PubMed
- 27668389 Full text @ Nat. Neurosci.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping