Although recent studies showed anti-PLA2R antibody plays a crucial role in idiopathic membranous nephropathy (IMN), detailed HLA mapping and interaction between the HLA genes and PLA2R1 have not been investigated in IMN. We genotyped across the PLA2R1 gene and the HLA region, using 183 IMN patients and 811 healthy controls. Five SNPs around the PLA2R1 gene were significantly associated with IMN. In addition to the two SNPs previously reported to be strongly associated with IMN, rs3749119 and rs35771982 (OR 3.02 and 2.93, P = 3.24E-14 and 4.64E-14, respectively), two novel intronic SNPs (rs2715928 and rs16844715) were also identified as IMN-associated SNPs (OR = 2.30 and 2.51, P = 3.15E-10 and 5.66E-13, respectively). In the HLA gene analysis, DRB1*1501 and DQB1*0602 were strongly associated with IMN (P = 1.14E-11 and 1.25E-11, respectively). The interaction was strongest between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the intronic SNP rs2715928 (OR = 17.53, P = 4.26E-26). Furthermore, positive interaction was also observed between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the missense SNP rs35771982 (OR = 15.91, P = 2.76E-29), which is in strong linkage disequilibrium with 5′UTR SNP rs3749119, and intronic SNP rs16844715 (OR = 15.91, P = 2.30E-26) for IMN. Neither HLA-DRB1*15:01 nor HLA-DQB1*06:02 was associated with steroid responsiveness, overall survival and renal survival during the observation period of mean 11 years though limited number of analysis.

The oxytocin receptor (OXTR) gene has been implicated as a risk gene for autism spectrum disorder (ASD)-a neurodevelopmental disorder with essential features of impairments in social communication and reciprocal interaction. The genetic associations between common variations in OXTR and ASD have been reported in multiple ethnic populations. However, little is known about the distribution of rare variations within OXTR in ASD patients. In this study, we resequenced the full length of OXTR in 105 ASD individuals using an approach that combined the power of next-generation sequencing technology, long-range PCR and DNA pooling. We demonstrated that rare variants with minor allele frequency as low as 0.05% could be reliably detected by our method. We identified 28 novel variants including potential functional variants in the intron region and one rare missense variant (R150S). We subsequently performed Sanger sequencing and validated five novel variants located in previously suggested candidate regions in ASD individuals. Further sequencing of 312 healthy subjects showed that the burden of rare variants is significantly higher in ASDs compared with healthy individuals. Our results support that the rare variation in OXTR gene might be involved in ASD.Human Genome Variation (2015) 2, 15024; doi:10.1038/hgv.2015.24; published online 30 July 2015 INTRODUCTIONOxytocin is a nine-amino-acid peptide that acts as a hormone in peripheral tissues and as a neuromodulator in the brain. This short peptide was first noted and studied for its effects in promoting uterine contractions during childbirth and stimulating milk ejection, and is currently widely used for labor induction. Beyond these well-documented functions, recent studies demonstrate that oxytocin also has a critical role in regulating a wide range of social behaviors including pair bonding, maternal parenting and formation of social memory, 1 whereas the molecular mechanisms remain largely unknown. Oxytocin is synthesized in the hypothalamus, an almond-sized region deep inside the brain, and is released into the blood or diffused to other brain regions through exocytosis. Oxytocin exerts its effect by activating its specific receptor, the oxytocin receptor (OXTR)-a G-protein-coupled receptor-which relays the messages to downstream effectors.

The associations of single nucleotide polymorphisms (SNPs) in PLA2R1 and HLA-DQA1, as well as HLA-DRB1*15:01-DQB1*06:02 haplotype with idiopathic membranous nephropathy (IMN) is well known. However, the primary associations of these loci still need to be determined. We used Japanese-specific SNP genotyping array and imputation using 2,048 sequenced Japanese samples to fine-map PLA2R1 region in 98 patients and 413 controls. The most significant SNPs were replicated in a separate sample set of 130 patients and 288 controls. A two-SNP haplotype of intronic and missense SNPs showed the strongest association. The intronic SNP is strongly associated with PLA2R1 expression in the Genotype-Tissue Expression (GTEx) database, and the missense SNP is predicted to alter peptide binding with HLA-DRB1*15:01 by the Immune Epitope Database (IEDB). In HLA region, we performed relative predispositional effect (RPE) tests and identified additional risk alleles in both HLA-DRB1 and HLA-DQB1. We collapsed the risk alleles in each of HLA-DRB1 and HLA-DQB1 into single risk alleles. Reciprocal conditioning of these collapsed risk alleles showed more residual significance for HLA-DRB1 collapsed risk than HLA-DQB1 collapsed risk. These results indicate that changes in the expression levels of structurally different PLA2R protein confer risk for IMN in the presence of risk HLA-DRB1 alleles.

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