TY - JOUR
T1 - Non-random mating, parent-of-origin, and maternal-fetal incompatibility effects in schizophrenia
AU - Kim, Yunjung
AU - Ripke, Stephan
AU - Kirov, George
AU - Sklar, Pamela
AU - Purcell, Shaun M.
AU - Owen, Michael J.
AU - O'Donovan, Michael C.
AU - Sullivan, Patrick F.
N1 - Funding Information:
Funding for recruitment was provided by the Janssen Research Foundation. Genotyping was funded by multiple grants to the Stanley Center for Psychiatric Research at the Broad Institute from the Stanley Medical Research Institute, The Merck Genome Research Foundation, and the Herman Foundation. Work at Cardiff University was funded by Medical Research Council Programme and Centre Grants. The funding bodies had no role in dictating the design of the study, the analysis, or any conclusions derived.
PY - 2013/1
Y1 - 2013/1
N2 - Although the association of common genetic variation in the extended MHC region with schizophrenia is the most significant yet discovered, the MHC region is one of the more complex regions of the human genome, with unusually high gene density and long-range linkage disequilibrium. The statistical test on which the MHC association is based is a relatively simple, additive model which uses logistic regression of SNP genotypes to predict case-control status. However, it is plausible that more complex models underlie this association. Using a well-characterized sample of trios, we evaluated more complex models by looking for evidence for: (a) non-random mating for HLA alleles, schizophrenia risk profiles, and ancestry; (b) parent-of-origin effects for HLA alleles; and (c) maternal-fetal genotype incompatibility in the HLA. We found no evidence for non-random mating in the parents of individuals with schizophrenia in terms of MHC genotypes or schizophrenia risk profile scores. However, there was evidence of non-random mating that appeared mostly to be driven by ancestry. We did not detect over-transmission of HLA alleles to affected offspring via the general TDT test (without regard to parent of origin) or preferential transmission via paternal or maternal inheritance. We evaluated the hypothesis that maternal-fetal HLA incompatibility may increase risk for schizophrenia using eight classical HLA loci. The most significant alleles were in HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 but none was significant after accounting for multiple comparisons. We did not find evidence to support more complex models of gene action, but statistical power may have been limiting.
AB - Although the association of common genetic variation in the extended MHC region with schizophrenia is the most significant yet discovered, the MHC region is one of the more complex regions of the human genome, with unusually high gene density and long-range linkage disequilibrium. The statistical test on which the MHC association is based is a relatively simple, additive model which uses logistic regression of SNP genotypes to predict case-control status. However, it is plausible that more complex models underlie this association. Using a well-characterized sample of trios, we evaluated more complex models by looking for evidence for: (a) non-random mating for HLA alleles, schizophrenia risk profiles, and ancestry; (b) parent-of-origin effects for HLA alleles; and (c) maternal-fetal genotype incompatibility in the HLA. We found no evidence for non-random mating in the parents of individuals with schizophrenia in terms of MHC genotypes or schizophrenia risk profile scores. However, there was evidence of non-random mating that appeared mostly to be driven by ancestry. We did not detect over-transmission of HLA alleles to affected offspring via the general TDT test (without regard to parent of origin) or preferential transmission via paternal or maternal inheritance. We evaluated the hypothesis that maternal-fetal HLA incompatibility may increase risk for schizophrenia using eight classical HLA loci. The most significant alleles were in HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 but none was significant after accounting for multiple comparisons. We did not find evidence to support more complex models of gene action, but statistical power may have been limiting.
KW - Human leukocyte antigens
KW - Maternal-fetal incompatibility
KW - Non-random mating
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=84871934504&partnerID=8YFLogxK
U2 - 10.1016/j.schres.2012.11.002
DO - 10.1016/j.schres.2012.11.002
M3 - Article
C2 - 23177929
AN - SCOPUS:84871934504
SN - 0920-9964
VL - 143
SP - 11
EP - 17
JO - Schizophrenia Research
JF - Schizophrenia Research
IS - 1
ER -