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Increased burden of...
Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
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Genovese, G. (author)
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Fromer, M. (author)
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Stahl, E. A. (author)
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Ruderfer, D. M. (author)
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Chambert, K. (author)
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- Landén, Mikael, 1966 (author)
- Karolinska Institutet,Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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Moran, J. L. (author)
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Purcell, S. M. (author)
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Sklar, P. (author)
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- Sullivan, P. F. (author)
- Karolinska Institutet
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- Hultman, C. M. (author)
- Karolinska Institutet
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McCarroll, S. A. (author)
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(creator_code:org_t)
- 2016-10-03
- 2016
- English.
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In: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 19:11, s. 1433-1441
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Abstract
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- By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 x 10(-10)). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- autism spectrum disorders
- of-function variants
- de-novo
- brain-development
- bipolar disorder
- genes
- mutations
- association
- translocation
- heritability
- Neurosciences & Neurology
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Genovese, G.
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Fromer, M.
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Stahl, E. A.
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Ruderfer, D. M.
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Chambert, K.
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Landén, Mikael, ...
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show more...
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Moran, J. L.
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Purcell, S. M.
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Sklar, P.
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Sullivan, P. F.
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Hultman, C. M.
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McCarroll, S. A.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Nature Neuroscie ...
- By the university
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University of Gothenburg
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Karolinska Institutet