RHD maternal-fetal genotype incompatibility increases schizophrenia susceptibility

Fetal events and obstetric complications are associated with schizophrenia. Here we report the results of a family-based candidate-gene study that assesses the role of maternal-fetal genotype incompatibility at the RHD locus in schizophrenia. We adapted the case-parent-trio log-linear modeling approach to test for RHD maternal-fetal genotype incompatibility and to distinguish this effect from a high-risk allele at or near the RHD locus and from a direct maternal effect alone. Eighty-eight patient-parent trios, 72 patient-mother pairs, and 21 patient-father pairs were genotyped at the RHD locus. Of the 181 patients, 62% were male and 81% were second born or later. Only three patients were born after prophylaxis against maternal isoimmunization had become common practice. There was significant evidence for an RHD maternal-fetal genotype incompatibility, and the incompatibility parameter was estimated at 2.6. There was no evidence to support linkage/association with schizophrenia at or near the RHD locus nor any evidence to support the role of maternal genotype effect alone. Our results replicate previous findings that implicate the RHD locus in schizophrenia, and the candidate-gene design of this study allows the elimination of alternative explanations for the role of this locus in disease. Thus, the present study provides increasing evidence that the RHD locus increases schizophrenia risk through a maternal-fetal genotype incompatibility mechanism that increases risk of an adverse prenatal environment (e.g., Rh incompatibility) rather than through linkage/association with the disorder, linkage disequilibrium with an unknown nearby susceptibility locus, or a direct maternal effect alone. This is the first candidate-gene study to explicitly test for and provide evidence of a maternal-fetal genotype incompatibility mechanism in schizophrenia.     

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val⁶⁶Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.     

闽南地区HLA-B27基因亚型与强直性脊柱炎相关性研究

目的对闽南地区人群中HLA-B27阳性标本进行回顾性调研及分型检测,探讨闽南地区HLAB27亚型分布情况,分析HLA-B27亚型与强直性脊柱炎(AS)的相关性。方法采用PCR-SBT(测序法)基因分型技术,对流式细胞术(FCM)检测为阳性的186例标本进行HLA-B*27基因分型。结果 186例HLA-B27阳性(FCM法)标本中,再用PCR-SBT法检测,HLA-B*27基因型均为阳性;而基因亚型分布,174例为B*27:04亚型,占93.5%,有8例B*27:05亚型,占4.3%,B*27:15亚型2例,占1.1%,另外B*27:06和B*27:07各1例,均占0.5%。186例中有103例确诊为AS患者,其中98例为B*27:04亚型,占95.1%,3例为B*27:05亚型,占2.9%,B*27:07和B*27:15亚型各1例,均占1.0%。结论闽南地区HLA-B27阳性的强直病患者以B*27:04为主,其次为B*27:05。AS患者与其他B27基因携带者,在亚型分布上没有明显的差异。     

Chimaeric load among sympatric social bacteria increases with genotype richness

The total productivity of social groups can be determined by interactions among their constituents. Chimaeric load—the reduction of group productivity caused by antagonistic within-group heterogeneity—may be common in heterogeneous microbial groups due to dysfunctional behavioural interactions between distinct individuals. However, some instances of chimaerism in social microbes can increase group productivity, thus making a general relationship between chimaerism and group-level performance non-obvious. Using genetically similar strains of the soil bacterium Myxococcus xanthus that were isolated from a single centimetre-scale patch of soil, we tested for a relationship between degree of chimaerism (genotype richness) and total group performance at social behaviours displayed by this species. Within-group genotype richness was found to correlate negatively with total group performance at most traits examined, including swarming in both predatory and prey-free environments and spore production during development. These results suggest that interactions between such neighbouring strains in the wild will tend to be mutually antagonistic. Negative correlations between group performance and average genetic distance among group constituents at three known social genes were not found, suggesting that divergence at other loci that govern social interaction phenotypes is responsible for the observed chimaeric load. The potential for chimaeric load to result from co-aggregation among even closely related neighbours may promote the maintenance and strengthening of kin discrimination mechanisms, such as colony-merger incompatibilities observed in M. xanthus. The findings reported here may thus have implications for understanding the evolution and maintenance of diversity in structured populations of soil microbes.     

Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women

Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p = 2.9 × 10⁻⁵ in women), with a significant gene-sex effect (p = 1.8 × 10⁻⁴). We studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p = 2.1 × 10⁻³ in women; p = 4.2 × 10⁻³ for gene-sex interaction). Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p = 8.8 × 10⁻⁷; p = 1.6 × 10⁻⁵ for gene-sex interaction). The female-specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease.     

Immune response increases predation risk

Why do individuals have an imperfect immune system? Most studies suggest trade‐offs associated with immunity and metabolism, and neglect ecological factors, such as predation. We provide one of the first experimental studies demonstrating a context‐dependent survival cost to immune activation. In the presence of a predator, immune‐challenged male field crickets showed significantly lower survival than controls, whilst there was no difference in a predator‐free environment. Immune‐challenged males spent more time outside their burrows and reacted slower to a simulated predator attack. We conclude that some costs of immunity are expressed via increased susceptibility to predation, indicating the importance of integrating the ecological context when investigating optimal investment in immunity.     

Allowing for missing data at highly polymorphic genes when testing for maternal, offspring and maternal-fetal genotype incompatibility effects

Genes can be associated with disease through an individual's inherited genotype, the maternal genotype or the interaction between these two. When the gene is highly polymorphic, it is more difficult to identify the gene's functional role than for less polymorphic loci, because different alleles at the locus may be associated with the disease through separate and joint effects from maternal and offspring genotypes. Family-based studies are used to test genetic associations because of their robustness to population stratification. However, parental genotype data are often missing, and omitting incompletely genotyped families is inefficient. Methods have been proposed to accommodate incomplete families in family-based association studies. They are not easily generalized to allow simultaneous examination of offspring allelic, maternal allelic and maternal-fetal genotype (MFG) incompatibility effects. Since many MFG incompatibility effects occur through matching between maternal and offspring's genotypes, we present an identity-by-state (IBS) framework to incorporate incomplete families in the MFG test when modeling genetic effects produced by a polymorphic gene. Using simulations, we examine the MFG test's performance with incomplete parental genotype data and an IBS framework. The MFG test using the IBS framework is immune to population stratification and efficiently uses information from incomplete families.     

Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia

Both neurocognitive deficits and schizophrenia are highly heritable. Genetic overlap between neurocognitive deficits and schizophrenia has been observed in both the general population and in the clinical samples. This study aimed to examine if the polygenic architecture of susceptibility to schizophrenia modified neurocognitive performance in schizophrenia patients. Schizophrenia polygenic risk scores (PRSs) were first derived from the Psychiatric Genomics Consortium (PGC) on schizophrenia, and then the scores were calculated in our independent sample of 1130 schizophrenia trios, who had PsychChip data and were part of the Schizophrenia Families from Taiwan project. Pseudocontrols generated from the nontransmitted parental alleles of the parents in these trios were compared with alleles in schizophrenia patients in assessing the replicability of PGC‐derived susceptibility variants. Schizophrenia PRS at the P‐value threshold (PT) of 0.1 explained 0.2% in the variance of disease status in this Han‐Taiwanese samples, and the score itself had a P‐value 0.05 for the association test with the disorder. Each patient underwent neurocognitive evaluation on sustained attention using the continuous performance test and executive function using the Wisconsin Card Sorting Test. We applied a structural equation model to construct the neurocognitive latent variable estimated from multiple measured indices in these 2 tests, and then tested the association between the PRS and the neurocognitive latent variable. Higher schizophrenia PRS generated at the PT of 0.1 was significantly associated with poorer neurocognitive performance with explained variance 0.5%. Our findings indicated that schizophrenia susceptibility variants modify the neurocognitive performance in schizophrenia patients.