Cis- and trans- loci influence expression of the schizophrenia susceptibility gene DTNBP1

Bray, Nicholas John ORCID: https://orcid.org/0000-0002-4357-574X, Holmans, Peter Alan ORCID: https://orcid.org/0000-0003-0870-9412, van den Bree, Marianne Bernadette ORCID: https://orcid.org/0000-0002-4426-3254, Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612, Elliston, Linda Anne, Hughes, Gareth, Richards, Alexander, Williams, Nigel Melville ORCID: https://orcid.org/0000-0003-1177-6931, Craddock, Nicholas John ORCID: https://orcid.org/0000-0003-2171-0610, Owen, Michael John ORCID: https://orcid.org/0000-0003-4798-0862 and O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379 2008. Cis- and trans- loci influence expression of the schizophrenia susceptibility gene DTNBP1. Human Molecular Genetics 17 (8) , pp. 1169-1174. 10.1093/hmg/ddn006

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Abstract

Susceptibility to complex disease appears to be partly mediated by heritable differences in gene expression. Where cis-acting effects on a gene's expression influence disease susceptibility, other genes containing polymorphism with a trans-acting effect on expression of that gene may also be expected to modulate risk. Use of the expression of an identified disease gene as an endophenotype for quantitative linkage analysis may therefore provide a powerful method for mapping loci that modulate disease susceptibility. We performed genome-wide linkage analysis on expression of dystrobrevin binding protein 1 (DTNBP1), a well-supported susceptibility gene for schizophrenia, in large CEPH pedigrees. We observed genome-wide significant evidence for linkage at the DTNBP1 locus on chromosome 6p22, and demonstrated that this reflects variable cis-acting effects on DTNBP1 expression. In addition, we observed genome-wide suggestive evidence for linkage of DTNBP1 expression to chromosome 8p, suggesting a locus that exerts a trans-acting effect on DTNBP1 expression. The region of linkage to DTNBP1 expression on chromosome 8 is contiguous with linkage findings based upon the clinical schizophrenia phenotype, and contains another well-supported schizophrenia susceptibility gene, neuregulin-1 (NRG1). Our data provide complementary evidence for chromosome 8p as a susceptibility locus for schizophrenia, and suggest that genetic variation within this region may influence risk, at least in part, through effects on DTNBP1 expression.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	R Medicine > R Medicine (General)
Publisher:	Oxford University Press
ISSN:	0964-6906
Last Modified:	04 Mar 2023 02:56
URI:	https://orca.cardiff.ac.uk/id/eprint/25790

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