Non-random mating, parent-of-origin, and maternal–fetal incompatibility effects in schizophrenia

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Abstract

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.

Introduction

Common genetic variation in the major histocompatibility complex (MHC) on 6p22.1 is a risk factor for many complex human diseases. The association of common genetic variation in the extended MHC region with schizophrenia is the most significant yet discovered (P ~ 10 12) (Ripke et al., 2011) and meets community standards in human genetics for replication (Chanock et al., 2007). However, the MHC region is one of the more complex regions of the human genome, with unusually high gene density and long-range linkage disequilibrium. As a result, the genome-wide significant evidence for association involves more than 100 SNPs, extends a very large distance (26–33 Mb), and encompasses around 300 genes.

The statistical test on which the MHC association is based is simple, using logistic regression of SNP genotypes to predict case–control status under an additive model. It is plausible that more complex models underlie this association. First, non-random mating (i.e., the tendency for mating partners to have greater phenotypic similarity than expected by chance) occurs for many physiological traits (Merikangas, 1982) as well as schizophrenia (Lichtenstein et al., 2006). Non-random mating can lead to complex biases in genomic studies (Redden and Allison, 2006) and may even be driven by genetic variation in the MHC region (Havlicek and Roberts, 2009). Second, parent-of-origin effects (variable genetic risk depending on the parent from which an allele is inherited) can occur in the MHC (Chao et al., 2010, Bassett, 2011). If this mechanism is operative, statistical models explicitly including such effects could assist in refining the currently broad and ill-defined MHC-schizophrenia association. Finally, maternal–fetal genotype incompatibility occurs when specific combinations of maternal and fetal genotypes yield an adverse prenatal environment (Childs et al., 2011). During pregnancy, maternal antibodies to paternal HLAs can be detected (Palmer, 2010). Since maternal antibodies to fetal antigens have been observed in a large proportion of healthy pregnancies, it is possible that maternal recognition or sensitization of paternally-derived fetal HLAs dissimilar to maternal HLAs may be beneficial for implantation and maintenance of pregnancy (Palmer et al., 2006). If paternally-derived fetal HLAs are similar to the maternal HLAs, maternal sensitization can fail to occur and lead to adverse fetal outcomes. Maternal–fetal genotype incompatibility may increase the risk of prenatal/obstetric complications (Verp et al., 1993, Cowan et al., 1994, Schneider et al., 1994, Ober et al., 1998), and there is some evidence that risk of schizophrenia may also be elevated (Palmer et al., 2006, Palmer, 2010).

Evaluation of these potentially more complex, MHC-themed models is difficult or impossible to do in case–control studies. Using a well-characterized sample of parent-affected offspring trios, we evaluated the evidence for: (a) non-random mating for HLA alleles and MHC SNPs, schizophrenia risk profiles, and ancestry; (b) parent-of-origin effects for HLA alleles and MHC SNPs; and (c) maternal–fetal genotype incompatibility in the HLA.

Section snippets

Subjects and genotyping

The study sample comprised 698 parent–offspring trio families from Bulgaria with 727 affected offspring (50.2% male). All subjects were genotyped with Affymetrix 6.0 chips at the Broad Institute (Ruderfer et al., 2011). We performed quality control (QC) steps in which we removed subjects with high genotype missing rates (> 2%) or high Mendelian errors per individual (> 2000 SNPs) along with SNPs with high missing rates (> 2%), strong deviation from Hardy–Weinberg Equilibrium (p < 1 × 10 6 in parents

Non-random mating

First, we tested for genetic similarity in founders of HapMap2 CEU, HapMap3 CEU, and our trio sample using imputed HLA alleles (Table S3) and SNPs (Table S4). To calibrate the method described in (Chaix et al., 2008) and replicate their finding, we repeated the non-random mating analysis of 5708 MHC SNPs (chr6: 29.6–33.3 Mb) with MAF ≥ 5% in HapMap2 CEU founders and confirmed the previously reported results (a slight but statistically significant dissimilarity in the MHC region, R =  0.064, p = 

Discussion

Using a relatively large and well-characterized trio sample, our study looked for evidence of non-random mating, parent-of-origin effects for HLA alleles, and maternal–fetal genotype incompatibility in the HLA. The results are consistent with three conclusions.

First, there was evidence of non-random mating by ancestry that appeared mostly to be driven by a subset of subjects who were ancestry outliers. We speculate that this could reflect within-group mating by minority groups within Bulgaria

Role of funding source

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.

Contributors

All authors reviewed and approved the final version of the manuscript. The corresponding authors had access to the full dataset.

Conflicts of interest

The authors report no conflicts.

Acknowledgements

The authors are grateful to the families who participated in the study.

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