Explore the vast range of titles available.

From whole organisms to individual cells, responses to environmental conditions are influenced by genetic makeup, where the effect of genetic variation on a trait depends on the environmental context. RNA-sequencing quantifies gene expression as a molecular trait, and is capable of capturing both genetic and environmental effects. In this study, we explore opportunities of using allele-specific expression (ASE) to discover cis-acting genotype-environment interactions (GxE)-genetic effects on gene expression that depend on an environmental condition. Treating 17 common, clinical traits as approximations of the cellular environment of 267 skeletal muscle biopsies, we identify 10 candidate environmental response expression quantitative trait loci (reQTLs) across 6 traits (12 unique gene-environment trait pairs; 10% FDR per trait) including sex, systolic blood pressure, and low-density lipoprotein cholesterol. Although using ASE is in principle a promising approach to detect GxE effects, replication of such signals can be challenging as validation requires harmonization of environmental traits across cohorts and a sufficient sampling of heterozygotes for a transcribed SNP. Comprehensive discovery and replication will require large human transcriptome datasets, or the integration of multiple transcribed SNPs, coupled with standardized clinical phenotyping.

Association of Transcription Factor 7-Like 2 ( TCF7L2 ) Variants With Type 2 Diabetes in a Finnish Sample Laura J. Scott 1 , Lori L. Bonnycastle 2 , Cristen J. Willer 1 , Andrew G. Sprau 2 , Anne U. Jackson 1 , Narisu Narisu 2 , William L. Duren 1 , Peter S. Chines 2 , Heather M. Stringham 1 , Michael R. Erdos 2 , Timo T. Valle 3 , Jaakko Tuomilehto 3 4 5 , Richard N. Bergman 6 , Karen L. Mohlke 7 , Francis S. Collins 2 and Michael Boehnke 1 1 Department of Biostatistics, School of Public Health, and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 2 Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 3 Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland 4 Department of Public Health, University of Helsinki, Helsinki, Finland 5 South Ostrobothnia Central Hospital, Seinäjoki, Finland 6 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 7 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina Address correspondence and reprint requests to Laura Scott, PhD, Department of Biostatistics, School of Public Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109-2029. E-mail: ljst{at}umich.edu Abstract Transcription factor 7-like 2 ( TCF7L2 ) is part of the Wnt signaling pathway. Genetic variants within TCF7L2 on chromosome 10q were recently reported to be associated with type 2 diabetes in Icelandic, Danish, and American (U.S.) samples. We previously observed a modest logarithm of odds score of 0.61 on chromosome 10q, ∼1 Mb from TCF7L2 , in the Finland-United States Investigation of NIDDM Genetics study. We tested the five associated TCF7L2 single nucleotide polymorphism (SNP) variants in a Finnish sample of 1,151 type 2 diabetic patients and 953 control subjects. We confirmed the association with the same risk allele ( P value <0.05) for all five SNPs. Our strongest results were for rs12255372 (odds ratio [OR] 1.36 [95% CI 1.15–1.61], P = 0.00026) and rs7903146 (1.33 [1.14–1.56], P = 0.00042). Based on the CEU HapMap data, we selected and tested 12 additional SNPs to tag SNPs in linkage disequilibrium with rs12255372. None of these SNPs showed stronger evidence of association than rs12255372 or rs7903146 (OR ≤1.26, P ≥ 0.0054). Our results strengthen the evidence that one or more variants in TCF7L2 are associated with increased risk of type 2 diabetes. FUSION, Finland-United States Investigation of NIDDM Genetics GIST, Genotype-IBD Sharing Test LD, linkage disequilibrium NGT, normal glucose tolerance SNP, single nucleotide polymorphism Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 15, 2006. Received March 14, 2006. DIABETES

Genetic Variation Near the Hepatocyte Nuclear Factor-4α Gene Predicts Susceptibility to Type 2 Diabetes Kaisa Silander 1 , Karen L. Mohlke 1 , Laura J. Scott 2 , Erin C. Peck 1 , Pablo Hollstein 1 , Andrew D. Skol 2 , Anne U. Jackson 2 , Panagiotis Deloukas 3 , Sarah Hunt 3 , George Stavrides 3 , Peter S. Chines 1 , Michael R. Erdos 1 , Narisu Narisu 1 , Karen N. Conneely 2 , Chun Li 2 , Tasha E. Fingerlin 2 , Sharanjeet K. Dhanjal 4 , Timo T. Valle 5 6 , Richard N. Bergman 7 , Jaakko Tuomilehto 5 6 8 , Richard M. Watanabe 4 , Michael Boehnke 2 and Francis S. Collins 1 1 Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 2 Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan 3 The Wellcome Trust Sanger Institute, Hinxton, U.K 4 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 5 Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland 6 Department of Biochemistry, National Public Health Institute, Helsinki, Finland 7 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 8 Department of Public Health, University of Helsinki, Helsinki, Finland Address correspondence and reprint requests to Michael Boehnke, PhD, Department of Biostatistics, School of Public Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109-2029. E-mail: boehnke{at}umich.edu Abstract The Finland-United States Investigation Of NIDDM Genetics (FUSION) study aims to identify genetic variants that predispose to type 2 diabetes by studying affected sibling pair families from Finland. Chromosome 20 showed our strongest initial evidence for linkage. It currently has a maximum logarithm of odds (LOD) score of 2.48 at 70 cM in a set of 495 families. In this study, we searched for diabetes susceptibility variant(s) at 20q13 by genotyping single nucleotide polymorphism (SNP) markers in case and control DNA pools. Of 291 SNPs successfully typed in a 7.5-Mb interval, the strongest association confirmed by individual genotyping was with SNP rs2144908, located 1.3 kb downstream of the primary β-cell promoter P2 of hepatocyte nuclear factor-4α ( HNF4A ). This SNP showed association with diabetes disease status (odds ratio [OR] 1.33, 95% CI 1.06–1.65, P = 0.011) and with several diabetes-related traits. Most of the evidence for linkage at 20q13 could be attributed to the families carrying the risk allele. We subsequently found nine additional associated SNPs spanning a 64-kb region, including the P2 and P1 promoters and exons 1–3. Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes. ASP, affected sibling pair EC, elderly control FUSION, Finland-United States Investigation of NIDDM Genetics GIST, Genotype-Identity-By-Descent Sharing Test HNF, hepatocyte nuclear factor IBD, identity by descent LD, linkage disequilibrium LOD, logarithm of odds MLS, maximum LOD score MODY, maturity-onset diabetes of the young OGTT, oral glucose tolerance test SNP, single nucleotide polymorphism Footnotes K.S. and K.L.M. contributed equally to this work. The current affiliation for K.S. is with the Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland. The current affiliation for C.L. is with the Department of Molecular Physiology and Biophysics, Program in Human Genetics, Vanderbilt University, Nashville, Tennessee. Posted on the World Wide Web at http://diabetes.diabetesjournals.org on 9 March 2004. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . Accepted January 13, 2004. Received September 10, 2003. DIABETES

Comprehensive Association Study of Type 2 Diabetes and Related Quantitative Traits With 222 Candidate Genes Kyle J. Gaulton 1 , Cristen J. Willer 2 , Yun Li 2 , Laura J. Scott 2 , Karen N. Conneely 2 , Anne U. Jackson 2 , William L. Duren 2 , Peter S. Chines 3 , Narisu Narisu 3 , Lori L. Bonnycastle 3 , Jingchun Luo 4 , Maurine Tong 3 , Andrew G. Sprau 3 , Elizabeth W. Pugh 5 , Kimberly F. Doheny 5 , Timo T. Valle 6 , Gonçalo R. Abecasis 2 , Jaakko Tuomilehto 6 7 8 , Richard N. Bergman 9 , Francis S. Collins 3 , Michael Boehnke 2 and Karen L. Mohlke 1 1 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 2 Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 3 Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 5 Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 6 Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland 7 Department of Public Health, University of Helsinki, Helsinki, Finland 8 South Ostrobothnia Central Hospital, Seinäjoki, Finland 9 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California Corresponding author: Karen Mohlke, mohlke{at}med.unc.edu Abstract OBJECTIVE— Type 2 diabetes is a common complex disorder with environmental and genetic components. We used a candidate gene–based approach to identify single nucleotide polymorphism (SNP) variants in 222 candidate genes that influence susceptibility to type 2 diabetes. RESEARCH DESIGN AND METHODS— In a case-control study of 1,161 type 2 diabetic subjects and 1,174 control Finns who are normal glucose tolerant, we genotyped 3,531 tagSNPs and annotation-based SNPs and imputed an additional 7,498 SNPs, providing 99.9% coverage of common HapMap variants in the 222 candidate genes. Selected SNPs were genotyped in an additional 1,211 type 2 diabetic case subjects and 1,259 control subjects who are normal glucose tolerant, also from Finland. RESULTS— Using SNP- and gene-based analysis methods, we replicated previously reported SNP-type 2 diabetes associations in PPARG , KCNJ11 , and SLC2A2 ; identified significant SNPs in genes with previously reported associations ( ENPP1 [rs2021966, P = 0.00026] and NRF1 [rs1882095, P = 0.00096]); and implicated novel genes, including RAPGEF1 (rs4740283, P = 0.00013) and TP53 (rs1042522, Arg72Pro, P = 0.00086), in type 2 diabetes susceptibility. CONCLUSIONS— Our study provides an effective gene-based approach to association study design and analysis. One or more of the newly implicated genes may contribute to type 2 diabetes pathogenesis. Analysis of additional samples will be necessary to determine their effect on susceptibility. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 4 August 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 21, 2008. Received December 11, 2007. DIABETES

Screening of 134 Single Nucleotide Polymorphisms (SNPs) Previously Associated With Type 2 Diabetes Replicates Association With 12 SNPs in Nine Genes Cristen J. Willer 1 , Lori L. Bonnycastle 2 , Karen N. Conneely 1 , William L. Duren 1 , Anne U. Jackson 1 , Laura J. Scott 1 , Narisu Narisu 2 , Peter S. Chines 2 , Andrew Skol 1 , Heather M. Stringham 1 , John Petrie 2 , Michael R. Erdos 2 , Amy J. Swift 2 , Sareena T. Enloe 2 , Andrew G. Sprau 2 , Eboni Smith 2 , Maurine Tong 2 , Kimberly F. Doheny 3 , Elizabeth W. Pugh 3 , Richard M. Watanabe 4 , Thomas A. Buchanan 5 , Timo T. Valle 6 , Richard N. Bergman 7 , Jaakko Tuomilehto 6 8 , Karen L. Mohlke 9 , Francis S. Collins 2 and Michael Boehnke 1 1 Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 2 Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 3 Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 4 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 5 Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California 6 Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland 7 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 8 Department of Public Health, University of Helsinki, Helsinki, Finland, and the South Ostrobothnia Central Hospital, Seinäjoki, Finland 9 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina Address correspondence and reprint requests to Michael Boehnke, PhD, Department of Biostatistics, School of Public Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109-2029. E-mail: boehnke{at}umich.edu Abstract More than 120 published reports have described associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. However, multiple studies of the same variant have often been discordant. From a literature search, we identified previously reported type 2 diabetes–associated SNPs. We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium ( r 2 > 0.8) with another typed SNP. Of the 114 SNPs examined, we followed up the 20 most significant SNPs ( P < 0.10) on an additional 384 case subjects and 366 control subjects from a population-based study in Finland. In the combined data, we replicated association ( P < 0.05) for 12 SNPs: PPARG Pro12Ala and His447, KCNJ11 Glu23Lys and rs5210, TNF −857, SLC2A2 Ile110Thr, HNF1A/TCF1 rs2701175 and GE117881_360, PCK1 −232, NEUROD1 Thr45Ala, IL6 −598, and ENPP1 Lys121Gln. The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association ( P = 0.012). We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample ( P = 0.03), although we also replicated 4 of 58 SNPs from genes that had only one previous report of association. FUSION, Finland-United States Investigation of NIDDM Genetics LD, linkage disequilibrium MAF, minor allele frequency MODY, maturity-onset diabetes of the young NGT, normal glucose tolerance SNP, single nucleotide polymorphism WHR, waist-to-hip ratio Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted September 18, 2006. Received April 7, 2006. DIABETES