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Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. Associations exceeding the genome-wide significance threshold (p<5 × 10−8) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10−19, odds ratio [OR] 1·84 [95% CI 1·61–2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10−14). This association is distinct from MHC associations with Epstein-Barr virus infection. To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).

Zhenglin Yang and colleagues use whole-exome sequencing to identify a rare variant in the FGD6 gene that is associated with the polypoidal choroidal vasculopathy subtype of wet age-related macular degeneration. They show that FGD6 regulates proangiogenic effects together with VEGF and that the mutation results in abnormal retinal vessel development. Polypoidal choroidal vasculopathy (PCV), a subtype of 'wet' age-related macular degeneration (AMD), constitutes up to 55% of cases of wet AMD in Asian patients. In contrast to the choroidal neovascularization (CNV) subtype, the genetic risk factors for PCV are relatively unknown. Exome sequencing analysis of a Han Chinese cohort followed by replication in four independent cohorts identified a rare c.986A>G (p.Lys329Arg) variant in the FGD6 gene as significantly associated with PCV ( P = 2.19 × 10 −16 , odds ratio (OR) = 2.12) but not with CNV ( P = 0.26, OR = 1.13). The intracellular localization of FGD6-Arg329 is distinct from that of FGD6-Lys329. In vitro , FGD6 could regulate proangiogenic activity, and oxidized phospholipids increased expression of FGD6 . FGD6-Arg329 promoted more abnormal vessel development in the mouse retina than FGD6-Lys329. Collectively, our data suggest that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.

Xue-Qing Yu, Jian-Jun Liu and colleagues report results of a genome-wide association study of IgA nephropathy in Han Chinese. They identify two new susceptibility loci at 8p23 and 17p13 and replicate previously reported signals in the MHC region and at 22q12. We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10 −11 , OR = 1.21; rs4227, P = 4.31 × 10 −10 , OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10 −14 , OR = 0.79) that implicated the genes encoding tumor necrosis factor ( TNFSF13 ) and α-defensin ( DEFA ) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10 −20 , OR = 1.34; rs1794275, P = 3.43 × 10 −13 , OR = 1.30; rs2523946, P = 1.74 × 10 −11 , OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10 −11 , OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN ( P = 0.003), proteinuria ( P = 0.025) and IgA levels ( P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation.

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10−14–6.94×10−10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.Xuling Chang et al. study whether low frequency variants are associated with leukocyte telomere length and whether these variants predispose to incident cancers and mortalities among East Asians. They find that three East Asian specific variants at POT1, TERF1 and STN1 loci are associated with leukocyte telomere length and report a mechanistic pathway linking TERF1, leukocyte telomere length and incident colon cancer.

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P =5.60 × 10 −22 ). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l −1 ( P =5.82 × 10 −21 ) in East Asians ( n =7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P= 6.19 × 10 −18 ), SLC44A4 Asp47Val (OR=1.27, P =1.08 × 10 −11 ) and FGD6 Gln257Arg (OR=0.87, P= 2.85 × 10 −8 ). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature. Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Here, the authors carry out a two-stage genome-wide association study for AMD and identify three new AMD risk loci, highlighting the shared and distinct genetic basis of the disease in East Asians and Europeans.

Sarah Dunstan, Chiea Chuen Khor and colleagues identify common variants in the HLA-DRB1 region associated with resistance to enteric fever. Individuals carrying the protective variants exhibit roughly five-fold higher resistance against developing this life-threatening infectious disease. Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C 1 . We conducted a genome-wide association study of 432 individuals with blood culture–confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10 −10 ), a marker mapping to the HLA class II region, in proximity to HLA - DQB1 and HLA - DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10 −11 ) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.

RNAseq data can be used to infer genetic variants, yet its use for estimating genetic population structure remains underexplored. Here, we construct a freely available computational tool (RGStraP) to estimate RNAseq-based genetic principal components (RG-PCs) and assess whether RG-PCs can be used to control for population structure in gene expression analyses. Using whole blood samples from understudied Nepalese populations and the Geuvadis study, we show that RG-PCs had comparable results to paired array-based genotypes, with high genotype concordance and high correlations of genetic principal components, capturing subpopulations within the dataset. In differential gene expression analysis, we found that inclusion of RG-PCs as covariates reduced test statistic inflation. Our paper demonstrates that genetic population structure can be directly inferred and controlled for using RNAseq data, thus facilitating improved retrospective and future analyses of transcriptomic data.