PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-20 (20)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
1.  GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers 
PLoS Genetics  2012;8(7):e1002791.
Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10−19) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10−8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10−4; rs455804: OR = 0.84, P = 6.92×10−3). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
Author Summary
Previous studies strongly suggest the importance of genetic susceptibility for hepatocellular carcinoma (HCC). However, the studies about genetic etiology on HBV–related HCC were limited. Our genome-wide association study included 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers for the discovery analysis. 2,112 HBV–positive HCC cases and 2,208 HBV carriers (the initial validation), and 1,021 cases and 1,491 HBV carriers (the second validation), were then analyzed for validation. The fourth independent samples of 1,298 cases and 1,026 controls were analyzed as replication. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 and rs455804 (GRIK1) on 21q21.3. HLA-DRB1 molecules play an important role in chronic HBV infection and progression to HCC. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
doi:10.1371/journal.pgen.1002791
PMCID: PMC3395595  PMID: 22807686
2.  Identification of new susceptibility loci for IgA nephropathy in Han Chinese 
Nature Communications  2015;6:7270.
IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10−10), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10−9) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10−9), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10−19), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10−19; rs12716641, P=9.53 × 10−9; rs9314614, P=4.25 × 10−9, multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.
IgA nephropathy is a major cause of end-stage renal disease in China, occurring at a high frequency in Asian populations. Here Li and colleagues conduct a four-stage genome-wide association study in a Chinese population, identifying novel loci and variants associated with disease risk.
doi:10.1038/ncomms8270
PMCID: PMC4458882  PMID: 26028593
3.  Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility 
Nature Communications  2015;6:6916.
Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.
Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here Yin et al. conduct a large trans-ethnic genome-wide meta-analysis and identify novel loci that contribute to population-specific susceptibility.
doi:10.1038/ncomms7916
PMCID: PMC4423213  PMID: 25903422
4.  Corrigendum: New loci and coding variants confer risk for age-related macular degeneration in East Asians 
Cheng, Ching-Yu | Yamashiro, Kenji | Jia Chen, Li | Ahn, Jeeyun | Huang, Lulin | Huang, Lvzhen | Cheung, Chui Ming G. | Miyake, Masahiro | Cackett, Peter D. | Yeo, Ian Y. | Laude, Augustinus | Mathur, Ranjana | Pang, Junxiong | Sim, Kar Seng | Koh, Adrian H. | Chen, Peng | Lee, Shu Yen | Wong, Doric | Chan, Choi Mun | Loh, Boon Kwang | Sun, Yaoyao | Davila, Sonia | Nakata, Isao | Nakanishi, Hideo | Akagi-Kurashige, Yumiko | Gotoh, Norimoto | Tsujikawa, Akitaka | Matsuda, Fumihiko | Mori, Keisuke | Yoneya, Shin | Sakurada, Yoichi | Iijima, Hiroyuki | Iida, Tomohiro | Honda, Shigeru | Lai, Timothy Yuk Yau | Tam, Pancy Oi Sin | Chen, Haoyu | Tang, Shibo | Ding, Xiaoyan | Wen, Feng | Lu, Fang | Zhang, Xiongze | Shi, Yi | Zhao, Peiquan | Zhao, Bowen | Sang, Jinghong | Gong, Bo | Dorajoo, Rajkumar | Yuan, Jian-Min | Koh, Woon-Puay | van Dam, Rob M. | Friedlander, Yechiel | Lin, Yin | Hibberd, Martin L. | Foo, Jia Nee | Wang, Ningli | Wong, Chang Hua | Tan, Gavin S. | Park, Sang Jun | Bhargava, Mayuri | Gopal, Lingam | Naing, Thet | Liao, Jiemin | Ong, Peng Guan | Mitchell, Paul | Zhou, Peng | Xie, Xuefeng | Liang, Jinlong | Mei, Junpu | Jin, Xin | Saw, Seang-Mei | Ozaki, Mineo | Mizoguchi, Takinori | Kurimoto, Yasuo | Woo, Se Joon | Chung, Hum | Yu, Hyeong-Gon | Shin, Joo Young | Park, Dong Ho | Kim, In Taek | Chang, Woohyok | Sagong, Min | Lee, Sang-Joon | Kim, Hyun Woong | Lee, Ji Eun | Li, Yi | Liu, Jianjun | Teo, Yik Ying | Heng, Chew Kiat | Lim, Tock Han | Yang, Suk-Kyun | Song, Kyuyoung | Vithana, Eranga N. | Aung, Tin | Bei, Jin Xin | Zeng, Yi Xin | Tai, E. Shyong | Li, Xiao Xin | Yang, Zhenglin | Park, Kyu-Hyung | Pang, Chi Pui | Yoshimura, Nagahisa | Wong, Tien Yin | Khor, Chiea Chuen
Nature Communications  2015;6:6817.
doi:10.1038/ncomms7817
PMCID: PMC4400603  PMID: 25817435
5.  A common variant near TGFBR3 is associated with primary open angle glaucoma 
Li, Zheng | Allingham, R. Rand | Nakano, Masakazu | Jia, Liyun | Chen, Yuhong | Ikeda, Yoko | Mani, Baskaran | Chen, Li-Jia | Kee, Changwon | Garway-Heath, David F. | Sripriya, Sarangapani | Fuse, Nobuo | Abu-Amero, Khaled K. | Huang, Chukai | Namburi, Prasanthi | Burdon, Kathryn | Perera, Shamira A. | Gharahkhani, Puya | Lin, Ying | Ueno, Morio | Ozaki, Mineo | Mizoguchi, Takanori | Krishnadas, Subbiah Ramasamy | Osman, Essam A. | Lee, Mei Chin | Chan, Anita S.Y. | Tajudin, Liza-Sharmini A. | Do, Tan | Goncalves, Aurelien | Reynier, Pascal | Zhang, Hong | Bourne, Rupert | Goh, David | Broadway, David | Husain, Rahat | Negi, Anil K. | Su, Daniel H | Ho, Ching-Lin | Blanco, Augusto Azuara | Leung, Christopher K.S. | Wong, Tina T. | Yakub, Azhany | Liu, Yutao | Nongpiur, Monisha E. | Han, Jong Chul | Hon, Do Nhu | Shantha, Balekudaru | Zhao, Bowen | Sang, Jinghong | Zhang, NiHong | Sato, Ryuichi | Yoshii, Kengo | Panda-Jonas, Songhomita | Ashley Koch, Allison E. | Herndon, Leon W. | Moroi, Sayoko E. | Challa, Pratap | Foo, Jia Nee | Bei, Jin-Xin | Zeng, Yi-Xin | Simmons, Cameron P. | Bich Chau, Tran Nguyen | Sharmila, Philomenadin Ferdinamarie | Chew, Merwyn | Lim, Blanche | Tam, Pansy O.S. | Chua, Elaine | Ng, Xiao Yu | Yong, Victor H.K. | Chong, Yaan Fun | Meah, Wee Yang | Vijayan, Saravanan | Seongsoo, Sohn | Xu, Wang | Teo, Yik Ying | Cooke Bailey, Jessica N. | Kang, Jae H. | Haines, Jonathan L. | Cheng, Ching Yu | Saw, Seang-Mei | Tai, E-Shyong | Richards, Julia E. | Ritch, Robert | Gaasterland, Douglas E. | Pasquale, Louis R. | Liu, Jianjun | Jonas, Jost B. | Milea, Dan | George, Ronnie | Al-Obeidan, Saleh A. | Mori, Kazuhiko | Macgregor, Stuart | Hewitt, Alex W. | Girkin, Christopher A. | Zhang, Mingzhi | Sundaresan, Periasamy | Vijaya, Lingam | Mackey, David A. | Wong, Tien Yin | Craig, Jamie E. | Sun, Xinghuai | Kinoshita, Shigeru | Wiggs, Janey L. | Khor, Chiea-Chuen | Yang, Zhenglin | Pang, Chi Pui | Wang, Ningli | Hauser, Michael A. | Tashiro, Kei | Aung, Tin | Vithana, Eranga N.
Human Molecular Genetics  2015;24(13):3880-3892.
Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.
doi:10.1093/hmg/ddv128
PMCID: PMC4459396  PMID: 25861811
6.  New loci and coding variants confer risk for age-related macular degeneration in East Asians 
Cheng, Ching-Yu | Yamashiro, Kenji | Jia Chen, Li | Ahn, Jeeyun | Huang, Lulin | Huang, Lvzhen | Cheung, Chui Ming G. | Miyake, Masahiro | Cackett, Peter D. | Yeo, Ian Y. | Laude, Augustinus | Mathur, Ranjana | Pang, Junxiong | Sim, Kar Seng | Koh, Adrian H. | Chen, Peng | Lee, Shu Yen | Wong, Doric | Chan, Choi Mun | Loh, Boon Kwang | Sun, Yaoyao | Davila, Sonia | Nakata, Isao | Nakanishi, Hideo | Akagi-Kurashige, Yumiko | Gotoh, Norimoto | Tsujikawa, Akitaka | Matsuda, Fumihiko | Mori, Keisuke | Yoneya, Shin | Sakurada, Yoichi | Iijima, Hiroyuki | Iida, Tomohiro | Honda, Shigeru | Lai, Timothy Yuk Yau | Tam, Pancy Oi Sin | Chen, Haoyu | Tang, Shibo | Ding, Xiaoyan | Wen, Feng | Lu, Fang | Zhang, Xiongze | Shi, Yi | Zhao, Peiquan | Zhao, Bowen | Sang, Jinghong | Gong, Bo | Dorajoo, Rajkumar | Yuan, Jian-Min | Koh, Woon-Puay | van Dam, Rob M. | Friedlander, Yechiel | Lin, Ying | Hibberd, Martin L. | Foo, Jia Nee | Wang, Ningli | Wong, Chang Hua | Tan, Gavin S. | Park, Sang Jun | Bhargava, Mayuri | Gopal, Lingam | Naing, Thet | Liao, Jiemin | Guan Ong, Peng | Mitchell, Paul | Zhou, Peng | Xie, Xuefeng | Liang, Jinlong | Mei, Junpu | Jin, Xin | Saw, Seang-Mei | Ozaki, Mineo | Mizoguchi, Takanori | Kurimoto, Yasuo | Woo, Se Joon | Chung, Hum | Yu, Hyeong-Gon | Shin, Joo Young | Park, Dong Ho | Kim, In Taek | Chang, Woohyok | Sagong, Min | Lee, Sang-Joon | Kim, Hyun Woong | Lee, Ji Eun | Li, Yi | Liu, Jianjun | Teo, Yik Ying | Heng, Chew Kiat | Lim, Tock Han | Yang, Suk-Kyun | Song, Kyuyoung | Vithana, Eranga N. | Aung, Tin | Bei, Jin Xin | Zeng, Yi Xin | Tai, E. Shyong | Li, Xiao Xin | Yang, Zhenglin | Park, Kyu-Hyung | Pang, Chi Pui | Yoshimura, Nagahisa | Yin Wong, Tien | Khor, Chiea Chuen
Nature Communications  2015;6:6063.
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.
doi:10.1038/ncomms7063
PMCID: PMC4317498  PMID: 25629512
7.  A Novel Splice-Site Mutation in ALS2 Establishes the Diagnosis of Juvenile Amyotrophic Lateral Sclerosis in a Family with Early Onset Anarthria and Generalized Dystonias 
PLoS ONE  2014;9(12):e113258.
The diagnosis of childhood neurological disorders remains challenging given the overlapping clinical presentation across subgroups and heterogeneous presentation within subgroups. To determine the underlying genetic cause of a severe neurological disorder in a large consanguineous Pakistani family presenting with severe scoliosis, anarthria and progressive neuromuscular degeneration, we performed genome-wide homozygosity mapping accompanied by whole-exome sequencing in two affected first cousins and their unaffected parents to find the causative mutation. We identified a novel homozygous splice-site mutation (c.3512+1G>A) in the ALS2 gene (NM_020919.3) encoding alsin that segregated with the disease in this family. Homozygous loss-of-function mutations in ALS2 are known to cause juvenile-onset amyotrophic lateral sclerosis (ALS), one of the many neurological conditions having overlapping symptoms with many neurological phenotypes. RT-PCR validation revealed that the mutation resulted in exon-skipping as well as the use of an alternative donor splice, both of which are predicted to cause loss-of-function of the resulting proteins. By examining 216 known neurological disease genes in our exome sequencing data, we also identified 9 other rare nonsynonymous mutations in these genes, some of which lie in highly conserved regions. Sequencing of a single proband might have led to mis-identification of some of these as the causative variant. Our findings established a firm diagnosis of juvenile ALS in this family, thus demonstrating the use of whole exome sequencing combined with linkage analysis in families as a powerful tool for establishing a quick and precise genetic diagnosis of complex neurological phenotypes.
doi:10.1371/journal.pone.0113258
PMCID: PMC4256290  PMID: 25474699
8.  A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival 
BMC Medical Genetics  2014;15:113.
Background
Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed.
Methods
We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999–2002 and in the United States 2001–2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model.
Results
In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0 ×10−8). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 5.24 ×10−8). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival.
Conclusions
The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-014-0113-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12881-014-0113-6
PMCID: PMC4411784  PMID: 25294155
Follicular lymphoma; Prognosis; Single nucleotide polymorphism; Genome-wide association study; Candidate gene study
9.  Large-scale genotyping identifies a new locus at 22q13.2 associated with female breast size 
Journal of medical genetics  2013;50(10):666-673.
Background
Individual differences in breast size are a conspicuous feature of variation in human females and have been associated with fecundity and advantage in selection of mates. To identify common variants that are associated with breast size, we conducted a large-scale genotyping association meta-analysis in 7,169 women of European descent across 3 independent sample collections with digital or screen film mammograms.
Methods
The samples consisted of the Swedish KARMA, LIBRO-1 and SASBAC studies genotyped on iCOGS, a custom illumina iSelect genotyping array comprising of 211,155 single nucleotide polymorphisms (SNPs) designed for replication and fine mapping of common and rare variants with relevance to breast, ovary and prostate cancer. Breast size of each subject was ascertained by measuring total breast area (mm2) on a mammogram.
Results
We confirm genome-wide significant associations at 8p11.23 (rs10086016, P = 1.3 × 10−14) and report a new locus at 22q13 (rs5995871, P = 3.2 × 10−8). The latter region contains the MKL1 gene, which has been shown to impact endogenous estrogen-receptor α transcriptional activity and is recruited on estradiol-sensitive genes. We also replicated previous GWAS findings for breast size at four other loci.
Conclusion
A new locus at 22q13 may be associated with female breast size.
doi:10.1136/jmedgenet-2013-101708
PMCID: PMC4159740  PMID: 23825393
Genome-wide association studies; population genetics; meta-analysis; breast size
10.  Combined linkage and family-based association analysis improves candidate gene detection in Genetic Analysis Workshop 18 simulation data 
BMC Proceedings  2014;8(Suppl 1):S29.
Because the genotype-phenotype correlation information is investigated differently by linkage and association analyses, various efforts have been made to model linkage and association jointly. However, joint modeling methods are usually computationally intensive; hence they cannot currently accommodate large pedigrees with dense markers. This article proposes a simple method to combine the linkage and association evidence with the aim of improving the detection power of disease susceptibility genes. Our detection power comparisons show that the combined linkage-association p values can improve remarkably the causal gene detection power in Genetic Analysis Workshop 18 simulation data.
doi:10.1186/1753-6561-8-S1-S29
PMCID: PMC4143774  PMID: 25519379
11.  Insights into the Genetic Structure and Diversity of 38 South Asian Indians from Deep Whole-Genome Sequencing 
PLoS Genetics  2014;10(5):e1004377.
South Asia possesses a significant amount of genetic diversity due to considerable intergroup differences in culture and language. There have been numerous reports on the genetic structure of Asian Indians, although these have mostly relied on genotyping microarrays or targeted sequencing of the mitochondria and Y chromosomes. Asian Indians in Singapore are primarily descendants of immigrants from Dravidian-language–speaking states in south India, and 38 individuals from the general population underwent deep whole-genome sequencing with a target coverage of 30X as part of the Singapore Sequencing Indian Project (SSIP). The genetic structure and diversity of these samples were compared against samples from the Singapore Sequencing Malay Project and populations in Phase 1 of the 1,000 Genomes Project (1 KGP). SSIP samples exhibited greater intra-population genetic diversity and possessed higher heterozygous-to-homozygous genotype ratio than other Asian populations. When compared against a panel of well-defined Asian Indians, the genetic makeup of the SSIP samples was closely related to South Indians. However, even though the SSIP samples clustered distinctly from the Europeans in the global population structure analysis with autosomal SNPs, eight samples were assigned to mitochondrial haplogroups that were predominantly present in Europeans and possessed higher European admixture than the remaining samples. An analysis of the relative relatedness between SSIP with two archaic hominins (Denisovan, Neanderthal) identified higher ancient admixture in East Asian populations than in SSIP. The data resource for these samples is publicly available and is expected to serve as a valuable complement to the South Asian samples in Phase 3 of 1 KGP.
Author Summary
Indians of South Asia has long been a population of interest to a wide audience, due to its unique diversity. We have deep-sequenced 38 individuals of Indian descent residing in Singapore (SSIP) in an effort to illustrate their diversity from a whole-genome standpoint. Indeed, among Asians in our population panel, SSIP was most diverse, followed by the Malays in Singapore (SSMP). Their diversity is further observed in the population's chromosome Y haplogroup and mitochondria haplogroup profiles; individuals with European-dominant haplogroups had greater proportion of European admixture. Among variants (single nucleotide polymorphism and small insertions/deletions) discovered in SSIP, 21.69% were novel with respect to previous sequencing projects. In addition, some 14 loss-of-function variants (LOFs) were associated to cancer, Type II diabetes, and cholesterol levels. Finally, D statistic test with ancient hominids concurred that there was gene flow to East Asians compared to South Asians.
doi:10.1371/journal.pgen.1004377
PMCID: PMC4022468  PMID: 24832686
12.  Genome-Wide Linkage, Exome Sequencing and Functional Analyses Identify ABCB6 as the Pathogenic Gene of Dyschromatosis Universalis Hereditaria 
PLoS ONE  2014;9(2):e87250.
Background
As a genetic disorder of abnormal pigmentation, the molecular basis of dyschromatosis universalis hereditaria (DUH) had remained unclear until recently when ABCB6 was reported as a causative gene of DUH.
Methodology
We performed genome-wide linkage scan using Illumina Human 660W-Quad BeadChip and exome sequencing analyses using Agilent SureSelect Human All Exon Kits in a multiplex Chinese DUH family to identify the pathogenic mutations and verified the candidate mutations using Sanger sequencing. Quantitative RT-PCR and Immunohistochemistry was performed to verify the expression of the pathogenic gene, Zebrafish was also used to confirm the functional role of ABCB6 in melanocytes and pigmentation.
Results
Genome-wide linkage (assuming autosomal dominant inheritance mode) and exome sequencing analyses identified ABCB6 as the disease candidate gene by discovering a coding mutation (c.1358C>T; p.Ala453Val) that co-segregates with the disease phenotype. Further mutation analysis of ABCB6 in four other DUH families and two sporadic cases by Sanger sequencing confirmed the mutation (c.1358C>T; p.Ala453Val) and discovered a second, co-segregating coding mutation (c.964A>C; p.Ser322Lys) in one of the four families. Both mutations were heterozygous in DUH patients and not present in the 1000 Genome Project and dbSNP database as well as 1,516 unrelated Chinese healthy controls. Expression analysis in human skin and mutagenesis interrogation in zebrafish confirmed the functional role of ABCB6 in melanocytes and pigmentation. Given the involvement of ABCB6 mutations in coloboma, we performed ophthalmological examination of the DUH carriers of ABCB6 mutations and found ocular abnormalities in them.
Conclusion
Our study has advanced our understanding of DUH pathogenesis and revealed the shared pathological mechanism between pigmentary DUH and ocular coloboma.
doi:10.1371/journal.pone.0087250
PMCID: PMC3911924  PMID: 24498303
13.  Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus 
Lu, Yi | Vitart, Veronique | Burdon, Kathryn P | Khor, Chiea Chuen | Bykhovskaya, Yelena | Mirshahi, Alireza | Hewitt, Alex W | Koehn, Demelza | Hysi, Pirro G | Ramdas, Wishal D | Zeller, Tanja | Vithana, Eranga N | Cornes, Belinda K | Tay, Wan-Ting | Tai, E Shyong | Cheng, Ching-Yu | Liu, Jianjun | Foo, Jia-Nee | Saw, Seang Mei | Thorleifsson, Gudmar | Stefansson, Kari | Dimasi, David P | Mills, Richard A | Mountain, Jenny | Ang, Wei | Hoehn, René | Verhoeven, Virginie J M | Grus, Franz | Wolfs, Roger | Castagne, Raphaële | Lackner, Karl J | Springelkamp, Henriët | Yang, Jian | Jonasson, Fridbert | Leung, Dexter Y L | Chen, Li J | Tham, Clement C Y | Rudan, Igor | Vatavuk, Zoran | Hayward, Caroline | Gibson, Jane | Cree, Angela J | MacLeod, Alex | Ennis, Sarah | Polasek, Ozren | Campbell, Harry | Wilson, James F | Viswanathan, Ananth C | Fleck, Brian | Li, Xiaohui | Siscovick, David | Taylor, Kent D | Rotter, Jerome I | Yazar, Seyhan | Ulmer, Megan | Li, Jun | Yaspan, Brian L | Ozel, Ayse B | Richards, Julia E | Moroi, Sayoko E | Haines, Jonathan L | Kang, Jae H | Pasquale, Louis R | Allingham, R Rand | Ashley-Koch, Allison | Mitchell, Paul | Wang, Jie Jin | Wright, Alan F | Pennell, Craig | Spector, Timothy D | Young, Terri L | Klaver, Caroline C W | Martin, Nicholas G | Montgomery, Grant W | Anderson, Michael G | Aung, Tin | Willoughby, Colin E | Wiggs, Janey L | Pang, Chi P | Thorsteinsdottir, Unnur | Lotery, Andrew J | Hammond, Christopher J | van Duijn, Cornelia M | Hauser, Michael A | Rabinowitz, Yaron S | Pfeiffer, Norbert | Mackey, David A | Craig, Jamie E | Macgregor, Stuart | Wong, Tien Y
Nature genetics  2013;45(2):155-163.
Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
doi:10.1038/ng.2506
PMCID: PMC3720123  PMID: 23291589
14.  Rare independent mutations in renal salt handling genes contribute to blood pressure variation 
Nature genetics  2008;40(5):592-599.
The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes -SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)- causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics, and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.
doi:10.1038/ng.118
PMCID: PMC3766631  PMID: 18391953
15.  A meta-analysis of genome-wide association studies of follicular lymphoma 
BMC Genomics  2012;13:516.
Background
B-cell non-Hodgkin lymphoma represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is one of the most common subtypes. Family and epidemiological studies suggest an important genetic role in the etiology of FL. In recent genome-wide association studies (GWAS) of FL, several genetic susceptibility loci have been identified on chromosome 6p21.33 (rs6457327) and 6p21.32 (rs10484561, rs2647012) in the human leukocyte antigen class I and class II regions. To identify new genetic variants and further elucidate the genetic basis of FL, a meta-analysis was performed of the top 1000 SNPs associated with FL risk from two GWAS in the US, Denmark and Sweden (592 cases, 1541 controls), with independent validation in 107 cases and 681 controls.
Results
rs9275517 and rs3117222 in the HLA class II region were validated and inversely associated with FL risk (rs9275517: OR = 0.63, 95% CI = 0.55-0.73, p = 4.03 × 10-11; rs3117222: OR = 0.66, 95% CI = 0.57-0.77, p = 1.45 × 10-7). rs9275517, which is in high linkage disequilibrium with rs2647012 (r2 = 0.9), was no longer associated with FL after conditioning on rs2647012. The rs3117222 association was independent of established FL SNPs, but not of the HLA-DPB1*0301 allele. Using publicly available gene expression profiles with matching genotype information, we found that rs3117222 also was significantly correlated with increased HLA-DPB1 expression.
Conclusions
By performing a meta-analysis of two GWAS of FL, we further validated the relevance of HLA-DPB1*0301 as a protective allele in the pathogenesis of FL. Moreover, the protective rs3117222 A allele correlated with increased levels of HLA-DPB1, suggesting a possible disease mechanism involving HLA-DPB1 expression regulation. Our results add further support to the major role of HLA genetic variation in the pathogenesis of FL.
doi:10.1186/1471-2164-13-516
PMCID: PMC3534234  PMID: 23025665
Follicular lymphoma (FL); Genome-wide association studies (GWAS); Human leukocyte antigen (HLA); Meta-analysis
16.  Genetic Variants in ER Cofactor Genes and Endometrial Cancer Risk 
PLoS ONE  2012;7(8):e42445.
Given that the transcriptional regulatory activity of estrogen receptor (ER) is modulated by its biochemical cofactors, genetic variation within the ER cofactor genes may alter cellular response to estrogen exposure and consequently modify the risk for endometrial cancer. We genotyped 685 tagging SNPs within 60 ER cofactor genes in 564 endometrial cancer cases and 1,510 controls from Sweden, and tested their associations with the risk of endometrial cancer. We investigated the associations of individual SNPs by using a trend test as well as multiple SNPs within a gene or gene complex by using multi-variant association analysis. No significant association was observed for any individual SNPs or genes, but a marginal association of the cumulative genetic variation of the NCOA2 complex as a whole (NCOA2, CARM1, CREBBP, PRMT1 and EP300) with endometrial cancer risk was observed (Padjusted = 0.033). However, the association failed to be replicated in an independent European dataset of 1265 cases and 5190 controls (P = 0.71). The results indicate that common genetic variants within ER cofactor genes are unlikely to play a significant role in endometrial cancer risk in European population.
doi:10.1371/journal.pone.0042445
PMCID: PMC3411617  PMID: 22876322
17.  A Comprehensive Association Analysis of Homocysteine Metabolic Pathway Genes in Singaporean Chinese with Ischemic Stroke 
PLoS ONE  2011;6(9):e24757.
Background
The effect of genetic factors, apart from 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms, on elevated plasma homocysteine levels and increasing ischemic stroke risk have not been fully elucidated. We conducted a comprehensive analysis of 25 genes involved in homocysteine metabolism to investigate association of common variants within these genes with ischemic stroke risk.
Methodology/Principal Findings
The study was done in two stages. In the initial study, SNP and haplotype-based association analyses were performed using 147 tagging Single Nucleotide Polymorphisms (SNPs) in 360 stroke patients and 354 non-stroke controls of Singaporean Chinese ethnicity. Joint association analysis of significant SNPs was then performed to assess the cumulative effect of these variants on ischemic stroke risk. In the replication study, 8 SNPs were selected for validation in an independent set of 420 matched case-control pairs of Singaporean Chinese ethnicity. SNP analysis from the initial study suggested 3 risk variants in the MTRR, SHMT1 and TCN2 genes which were moderately associated with ischemic stroke risk, independent of known stroke risk factors. Although the replication study failed to support single-SNP associations observed in the initial study, joint association analysis of the 3 variants in combined initial and replication samples revealed a trend of elevated risk with an increased number of risk alleles (Joint Ptrend = 1.2×10−6).
Conclusions
Our study did not find direct evidence of associations between any single polymorphisms of homocysteine metabolic pathway genes and ischemic stroke, but suggests that the cumulative effect of several small to moderate risk variants from genes involved in homocysteine metabolism may jointly confer a significant impact on ischemic stroke risk.
doi:10.1371/journal.pone.0024757
PMCID: PMC3174208  PMID: 21935458
18.  GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma 
PLoS Genetics  2011;7(4):e1001378.
Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL–associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10−21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10−12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10−15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10−7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.
Author Summary
Earlier studies have established a marker rs10484561, in the HLA class II region on 6p21.32, associated with increased follicular lymphoma (FL) risk. Here, in a three-stage genome-wide association study of 1,428 FL cases and 6,581 controls, we identified a second independent FL–associated marker on 6p21.32, rs2647012, located 962 bp away from rs10484561. The associations at two SNPs remained genome-wide significant after mutual adjustment. Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct lineage from that of rs10484561 and tags a novel allele with an opposite, protective effect on FL risk. Moreover, in an analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma. Our results reveal the presence of allelic heterogeneity at 6p21.32 in FL risk and suggest a shared genetic etiology with the common diffuse large B-cell lymphoma subtype.
doi:10.1371/journal.pgen.1001378
PMCID: PMC3080853  PMID: 21533074
19.  Apolipoprotein C3 Gene Variants in Nonalcoholic Fatty Liver Disease 
The New England journal of medicine  2010;362(12):1082-1089.
BACKGROUND
Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown.
METHODS
In 95 healthy Asian Indian men, a group known to have a high prevalence of non-alcoholic fatty liver disease, we genotyped two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) that are known to be associated with hypertriglyceridemia (rs2854116 [T-455C] and rs2854117 [C-482T]). Plasma apolipoprotein C3 concentrations, insulin sensitivity, and hepatic triglyceride content were measured. We also measured plasma triglyceride concentrations and retinyl fatty acid ester absorption as well as plasma triglyceride clearance after oral and intravenous fat-tolerance tests. Liver triglyceride content and APOC3 genotypes were also assessed in a group of 163 healthy non–Asian Indian men.
RESULTS
Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wild-type homozygotes. They also had a 60% increase in the fasting plasma triglyceride concentration, an increase by a factor of approximately two in the plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance. The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P<0.001). The subjects with nonalcoholic fatty liver disease had marked insulin resistance. A validation study involving non–Asian Indian men confirmed the association between APOC3 variant alleles and nonalcoholic fatty liver disease.
CONCLUSIONS
The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.
doi:10.1056/NEJMoa0907295
PMCID: PMC2976042  PMID: 20335584
20.  Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae 
PLoS Genetics  2009;5(2):e1000365.
It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.
Author Summary
Isolated populations have contributed to the discovery of loci with simple Mendelian segregation and large effects on disease risk or trait variation. We hypothesized that the use of isolated populations might also facilitate the discovery of common alleles contributing to complex traits with relatively larger effects. However, the use of association analyses to map common loci influencing trait variation in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We developed an analytic strategy to perform genome-wide association studies in an inbred family containing over 2,800 individuals from the island of Kosrae, Federated States of Micronesia. No alleles with large effect were observed with strong statistical support in any of the 15 traits examined, suggesting that the contribution of individual common variants to complex trait variation in Kosraens is typically not much greater than that observed in other populations. We show that the effects of many loci previously identified in Caucasian populations are indistinguishable in Caucasians and Kosraens, despite very different population genetics and environmental influences.
doi:10.1371/journal.pgen.1000365
PMCID: PMC2628735  PMID: 19197348

Results 1-20 (20)