Non-random mating, parent-of-origin, and maternal–fetal incompatibility effects in schizophrenia
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.
References (32)
- et al.
A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals
Am. J. Hum. Genet.
(2009) - et al.
MHC-correlated mate choice in humans: a review
Psychoneuroendocrinology
(2009) - et al.
HLA-B maternal–fetal genotype matching increases risk of schizophrenia
Am. J. Hum. Genet.
(2006) - et al.
PLINK: a tool set for whole-genome association and population-based linkage analyses
Am. J. Hum. Genet.
(2007) - et al.
Integrating common and rare genetic variation in diverse human populations
Nature
(2010) Parental origin, DNA structure, and the schizophrenia spectrum
Am. J. Psychiatry
(2011)- et al.
Controlling the false discovery rate - a practical and powerful approach to multiple testing
J. R. Stat. Soc. B.
(1995) - et al.
Overview of the MHC fine mapping data
Diabetes Obes. Metab.
(2009) - et al.
Is mate choice in humans MHC-dependent?
PLoS Genet.
(2008) - et al.
Replicating genotype–phenotype associations
Nature
(2007)
Parent-of-origin effects at the major histocompatibility complex in multiple sclerosis
Hum. Mol. Genet.
Modeling maternal–offspring gene–gene interactions: the extended-MFG test
Genet. Epidemiol.
Detection of intergenerational genetic effects with application to hla-B matching as a risk factor for schizophrenia
Hum. Hered.
Maternal–fetal Hla sharing and risk of newborn encephalopathy and seizures — a pilot-study
J. Child Neurol.
Absence of evidence for MHC-dependent mate selection within HapMap populations
PLoS Genet.
QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies
Cited by (1)
Excess of homozygosity in the major histocompatibility complex in schizophrenia
2014, Human Molecular Genetics
- 1
Equal contributions.