Human Genetics And Molecular Medicine - Research Publications

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Author: search.filters.author.Singh, J.R.

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    Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India
    (American Diabetes Association Inc., 2013) Saxena, R.; Saleheen, D.; Been, L.F.; Garavito, M.L.; Braun, T.; Bjonnes, A.; Young, R.; Ho, W.K.; Rasheed, A.; Frossard, P.; Sim, X.; Hassanali, N.; Radha, V.; Chidambaram, M.; Liju, S.; Rees, S.D.; Ng, D.P.-K.; Wong, T.-Y.; Yamauchi, T.; Hara, K.; Tanaka, Y.; Hirose, H.; McCarthy, M.I.; Morris, A.P.; Basit, A.; Barnett, A.H.; Katulanda, P.; Matthews, D.; Mohan, V.; Wander, G.S.; Singh, J.R.; Mehra, N.K.; Ralhan, S.; Kamboh, M.I.; Mulvihill, J.J.; Maegawa, H.; Tobe, K.; Maeda, S.; Cho, Y.S.; Ta
    We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10-3) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10-4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 ? 10-8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10-3) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10-4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10-5 to < 10-7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis. ? 2013 by the American Diabetes Association.
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    Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes
    (Nature Publishing Group, 2016) Imamura, M.; Takahashi, A.; Yamauchi, T.; Hara, K.; Yasuda, K.; Grarup, N.; Zhao, W.; Wang, X.; Huerta-Chagoya, A.; Hu, C.; Moon, S.; Long, J.; Kwak, S.H.; Rasheed, A.; Saxena, R.; Ma, R.C.W.; Okada, Y.; Iwata, M.; Hosoe, J.; Shojima, N.; Iwasaki, M.; Fujita, H.; Suzuki, K.; Danesh, J.; J?rgensen, T.; J?rgensen, M.E.; Witte, D.R.; Brandslund, I.; Christensen, C.; Hansen, T.; Mercader, J.M.; Flannick, J.; Moreno-Mac?as, H.; Burtt, N.P.; Zhang, R.; Kim, Y.J.; Zheng, W.; Singh, J.R.; Tam, C.H.T.; H
    Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 ? 10-8), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities. ? 2016, Nature Publishing Group. All rights reserved.
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    Directory of human genetic services in India - 2007
    (2010) Singh, J.R.; Singh, A.R.; Singh, A.R.
    [No abstract available]
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    A low frequency variant within the GWAS locus of MTNR1B affects fasting glucose concentrations: Genetic risk is modulated by obesity
    (2012) Been, L.F.; Hatfield, J.L.; Shankar, A.; Aston, C.E.; Ralhan, S.; Wander, G.S.; Mehra, N.K.; Singh, J.R.; Mulvihill, J.J.; Sanghera, D.K.
    Two common variants (rs1387153, rs10830963) in MTNR1B have been reported to have independent effects on fasting blood glucose (FBG) levels with increased risk to type 2 diabetes (T2D) in recent genome-wide association studies (GWAS). In this investigation, we report the association of these two variants, and an additional variant (rs1374645) within the GWAS locus of MTNR1B with FBG, 2h glucose, insulin resistance (HOMA IR), ?-cell function (HOMA B), and T2D in our sample of Asian Sikhs from India. Our cohort comprised 2222 subjects [1201 T2D, 1021 controls]. None of these SNPs was associated with T2D in this cohort. Our data also could not confirm association of rs1387153 and rs10830963 with FBG phenotype. However, upon stratifying data according to body mass index (BMI) (low ? 25 kg/m2 and high > 25 kg/m2) in normoglycemic subjects (n = 1021), the rs1374645 revealed a strong association with low FBG levels in low BMI group (? = -0.073, p = 0.002, Bonferroni p = 0.01) compared to the high BMI group (? = 0.015, p = 0.50). We also detected a strong evidence of interaction between rs1374645 and BMI with respect to FBG levels (p = 0.002). Our data provide new information about the significant impact of another MTNR1B variant on FBG levels that appears to be modulated by BMI. Future confirmation on independent datasets and functional studies will be required to define the role of this variant in fasting glucose variation. ? 2011.
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    A novel 7 bp deletion in PRPF31 associated with autosomal dominant retinitis pigmentosa with incomplete penetrance in an Indian family
    (2012) Saini, S.; Robinson, P.N.; Singh, J.R.; Vanita, V.
    To localize and identify the gene linked with non-syndromic autosomal dominant retinitis pigmentosa (adRP) with high but not complete penetrance in an Indian family. A detailed family history and clinical data were recorded. A genome-wide scan by 2-point linkage analysis using nearly 400 fluorescently labeled microsatellite markers in combination with multipoint lod score and haplotype analysis was carried out. Mutation screening was performed in the candidate gene by bidirectional sequence analysis of the amplified products. A maximum 2-point lod score of 3.553 at theta = 0.0 was obtained with marker D19S572. Haplotype analysis placed the RP locus distal to marker D19S572, in close proximity to the gene for pre-mRNA processing factor 31 (PRPF31) at 19q13.42. Mutation screening in all 14 exonic regions and adjacent flanking intronic sequences of PRPF31 revealed a novel 7 bp deletion, c.59_65del7 (p.Gly20AlafsX43), in the first coding exon of PRPF31. This leads to a premature termination codon (PTC) in the next exon, 43 amino acids downstream. The observed 7 bp deletion in PRPF31 was identified in all the tested 10 affected members and in an unaffected individual, consistent with a high, but not the complete penetrance of c.59_65del7 (p.Gly20AlafsX43). This deletion was not observed in other tested six unaffected family members or in 100 ethnically matched control subjects. The present study describes mapping of a locus for non-syndromic adRP at 19q13.42 (RP11 locus) in a family of Indian origin and identifies a novel deletion, c.59_65del7, in PRPF31 within the mapped interval. Since the mutant PRPF31 is truncated relatively close to the N-terminus of the protein, haploinsufficiency rather than aberrant protein formation is likely to be the underlying mechanism of the disease. The present findings further substantiate the role of PRPF31 that encodes a component of the spliceosome complex in relation to ADRP. ? 2012 Elsevier Ltd.