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1. Low-Frequency Variants in HMGA1 Are Not Associated With Type 2 Diabetes Risk

Author

Eleftheria Zeggini, Anna Gloyn, Michael Weedon, Torben Jørgensen, Amanda Bennett, Yurii Aulchenko, Andrew Hattersley, Peter P Pramstaller, Christian Dina, Michel Marre, Lena Carlsson Ekander, Claudia Langenberg, Mario Falchi, Peter Jacobson, Rafn Benediktsson, Philippe Froguel, Cornelia Van Duijn, David Couper, Jana Van Vliet-Ostaptchouk, Winston Hide, Francois Pattou, Barbara Heude, Odile POULAIN-GODEFROY, Loic Yengo, Thomas Meitinger, Richard Bergman, Cecilia Lindgren, Igor Rudan, and Erasmus MC other

Subjects
0303 health sciences, medicine.medical_specialty, biology, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Locus (genetics), Genome-wide association study, Genetics/Genomes/Proteomics/Metabolomics, Disease, Type 2 diabetes, medicine.disease, 3. Good health, 03 medical and health sciences, Insulin receptor, 0302 clinical medicine, Insulin resistance, Endocrinology, SDG 3 - Good Health and Well-being, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, biology.protein, Family history, 030304 developmental biology
Abstract

It has recently been suggested that the low-frequency c.136–14_136–13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136–14_136–13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136–14_136–13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.

Published
2012

2. A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data

Author

Anna Gloyn, Eric Gamazon, Benjamin Glaser, Adam Locke, E Shyong Tai, Jennifer Asimit, Inga Prokopenko, John Blangero, Dan Nicolae, Christian Fuchsberger, Jennifer Below, Mark Seielstad, Mark McCarthy, Cecilia Lindgren, Xueling Sim, Mohammad Kamran Ikram, and Other departments

Subjects
Genotype, Bioinformatics, LOCI, Computational biology, Biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, DNA sequencing, 03 medical and health sciences, CODING VARIANTS, Missing heritability problem, Genetics, SNP, Exome, GENOME-WIDE ASSOCIATION, COMMON, Genotyping, Exome sequencing, Imputation, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Genetics & Heredity, AFRICAN-AMERICANS, 08 Information And Computing Sciences, 0303 health sciences, Science & Technology, Methodology Article, 030305 genetics & heredity, Rare variant, GENETIC-VARIATION, High-Throughput Nucleotide Sequencing, T2D-Genes Consortium, 11 Medical And Health Sciences, 06 Biological Sciences, Exome chip, SNP genotyping, Biotechnology & Applied Microbiology, DISEASES, POPULATIONS, Life Sciences & Biomedicine, Combined approach, PROJECT, Imputation (genetics), Biotechnology
Abstract

Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF

Published
2015

3. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women

Author

Amelie Bonnefond, Nancy Heard-Costa, Eleftheria Zeggini, Anna Gloyn, LAURA CRISPONI, Eco De Geus, Michael Weedon, Torben Jørgensen, Jaakko Kaprio, Iva Miljkovic, Amanda Bennett, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Christian Dina, Sophie Visvikis-Siest, Udo Seedorf, Vilmundur Gudnason, Michael Marmot, Mika Kivimaki, Mary Feitosa, Danielle Posthuma, Claudia Langenberg, Stavroula Kanoni, Cyrus Cooper, Meena Kumari, Peter Kovacs, Debbie A Lawlor, Inga Prokopenko, Rafn Benediktsson, Stephen Kritchevsky, Philippe Froguel, Cornelia Van Duijn, Nita Forouhi, Anne B. Newman, Ko Willems van Dijk, John Carr, Reedik Mägi, Sutapa Mukherjee, Lyle John Palmer, Francois Pattou, L. Adrienne Cupples, Paul Franks, Paul Elliott, Albert Vernon Smith, MANUELA UDA, Kirsten Ohm Kyvik, Manuel Serrano Ríos, Richard Bergman, Gonneke Willemsen, Cecilia Lindgren, Igor Rudan, Human genetics, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Institute for Molecular Medicine Finland, Research Group Ripatti Samuli, Hjelt Institute (-2014), Department of Public Health, Biostatistics Helsinki, Complex Disease Genetics, Genetic Epidemiology, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, GIANT Consortium, MAGIC Consortium, GLGC Consortium, Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, AU., Wheeler, E., Glazer, NL., Bouatia-Naji, N., Gloyn, AL., Lindgren, CM., Mägi, R., Morris, AP., Randall, J., Johnson, T., Elliott, P., Rybin, D., Thorleifsson, G., Steinthorsdottir, V., Henneman, P., Grallert, H., Dehghan, A., Hottenga, JJ., Franklin, CS., Navarro, P., Song, K., Goel, A., Perry, JR., Egan, JM., Lajunen, T., Grarup, N., Sparsø, T., Doney, A., Voight, BF., Stringham, HM., Li, M., Kanoni, S., Shrader, P., Cavalcanti-Proença, C., Kumari, M., Qi, L., Timpson, NJ., Gieger, C., Zabena, C., Rocheleau, G., Ingelsson, E., An, P., O'Connell, J., Luan£££Jian'an£££ J., Elliott, A., McCarroll, SA., Payne, F., Roccasecca, RM., Pattou, F., Sethupathy, P., Ardlie, K., Ariyurek, Y., Balkau, B., Barter, P., Beilby, JP., Ben-Shlomo, Y., Benediktsson, R., Bennett, AJ., Bergmann, S., Bochud, M., Boerwinkle, E., Bonnefond, A., Bonnycastle, LL., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, SJ., Charpentier, G., Chen, YD., Chines, P., Clarke, R., Coin, LJ., Cooper, MN., Cornelis, M., Crawford, G., Crisponi, L., Day, IN., de Geus EJ., Delplanque, J., Dina, C., Erdos, MR., Fedson, AC., Fischer-Rosinsky, A., Forouhi, NG., Fox, CS., Frants, R., Franzosi, MG., Galan, P., Goodarzi, MO., Graessler, J., Groves, CJ., Grundy, S., Gwilliam, R., Gyllensten, U., Hadjadj, S., Hallmans, G., Hammond, N., Han, X., Hartikainen, AL., Hassanali, N., Hayward, C., Heath, SC., Hercberg, S., Herder, C., Hicks, AA., Hillman, DR., Hingorani, AD., Hofman, A., Hui, J., Hung, J., Isomaa, B., Johnson, PR., Jørgensen, T., Jula, A., Kaakinen, M., Kaprio, J., Kesaniemi, YA., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, KO., Lathrop, GM., Lawlor, DA., Le Bacquer, O., Lecoeur, C., Li, Y., Lyssenko, V., Mahley, R., Mangino, M., Manning, AK., Martínez-Larrad£££María Teresa£££ MT., McAteer, JB., McCulloch, LJ., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, BD., Morken, MA., Mukherjee, S., Naitza, S., Narisu, N., Neville, MJ., Oostra, BA., Orrù, M., Pakyz, R., Palmer, CN., Paolisso, G., Pattaro, C., Pearson, D., Peden, JF., Pedersen, NL., Perola, M., Pfeiffer, AF., Pichler, I., Polasek, O., Posthuma, D., Potter, SC., Pouta, A., Province, MA., Psaty, BM., Rathmann, W., Rayner, NW., Rice, K., Ripatti, S., Rivadeneira, F., Roden, M., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, AA., Scheet, P., Scott, LJ., Seedorf, U., Sharp, SJ., Shields, B., Sigurðsson, G., Sijbrands, EJ., Silveira, A., Simpson, L., Singleton, A., Smith, NL., Sovio, U., Swift, A., Syddall, H., Syvänen, AC., Tanaka, T., Thorand, B., Tichet, J., Tönjes, A., Tuomi, T., Uitterlinden, AG., van Dijk KW., van Hoek, M., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, PJ., Walley, A., Walters, GB., Ward, KL., Watkins, H., Weedon, MN., Wild, SH., Willemsen, G., Witteman, JC., Yarnell, JW., Zeggini, E., Zelenika, D., Zethelius, B., Zhai, G., Zhao, JH., Zillikens, MC., Borecki, IB., Loos, RJ., Meneton, P., Magnusson, PK., Nathan, DM., Williams, GH., Hattersley, AT., Silander, K., Salomaa, V., Smith, GD., Bornstein, SR., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, AR., Cooper, C., Dedoussis, GV., Serrano-Ríos, M., Morris, AD., Lind, L., Palmer, LJ., Hu, FB., Franks, PW., Ebrahim, S., Marmot, M., Kao, WH., Pankow, JS., Sampson, MJ., Kuusisto, J., Laakso, M., Hansen, T., Pedersen, O., Pramstaller, PP., Wichmann, HE., Illig, T., Rudan, I., Wright, AF., Stumvoll, M., Campbell, H., Wilson, JF., Hamsten, A., Bergman, RN., Buchanan, TA., Collins, FS., Mohlke, KL., Tuomilehto, J., Valle, TT., Altshuler, D., Rotter, JI., Siscovick, DS., Penninx, BW., Boomsma, ID., Deloukas, P., Spector, TD., Frayling, TM., Ferrucci, L., Kong, A., Thorsteinsdottir, U., Stefansson, K., van Duijn CM., Aulchenko, YS., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, MR., Waterworth, DM., Vollenweider, P., Peltonen, L., Mooser, V., Abecasis, RG., Wareham, NJ., Sladek, R., Froguel, P., Watanabe, RM., Meigs, JB., Groop, L., Boehnke, M., McCarthy, MI., Florez, JC., Barroso£££Inês£££ I., Feitosa, Mary [0000-0002-0933-2410], Heard-Costa, Nancy [0000-0001-9730-0306], Newman, Anne B [0000-0002-0106-1150], Miljkovic, Iva [0000-0002-3155-9777], Kritchevsky, Stephen B [0000-0003-3336-6781], Carr, J Jeffrey [0000-0002-4398-8237], Gudnason, Vilmunder [0000-0001-5696-0084], Cupples, L Adrienne [0000-0003-0273-7965], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)

Subjects
Male, Netherlands Twin Register (NTR), Cancer Research, Adipose tissue, Genome-wide association study, QH426-470, FTO gene, Body Mass Index, 0302 clinical medicine, Genetics (clinical), TISSUE DISTRIBUTION, GENE-EXPRESSION, 2. Zero hunger, ATHEROSCLEROSIS MESA, 0303 health sciences, INSULIN-RESISTANCE, Sex Characteristics, MAGIC Consortium, Adult, Aged, Cytokines/genetics, European Continental Ancestry Group, Female, Genome-Wide Association Study, HapMap Project, Humans, Intra-Abdominal Fat, Lysophospholipase/genetics, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proteins/genetics, Subcutaneous Fat, Abdominal, 3142 Public health care science, environmental and occupational health, CARDIOVASCULAR-DISEASE, OBESITY, Cytokines, Medicine, Lysophospholipase, Research Article, medicine.medical_specialty, Waist, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 030209 endocrinology & metabolism, HIP RATIO, Biology, White People, GLGC Consortium, 03 medical and health sciences, Insulin resistance, Internal medicine, GIANT Consortium, medicine, Genetics, CORONARY-HEART-DISEASE, ddc:610, Molecular Biology, PERICARDIAL FAT, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0604 Genetics, Proteins, nutritional and metabolic diseases, medicine.disease, Obesity, Endocrinology, RISK-FACTORS, Body mass index, Developmental Biology
Abstract

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits., Author Summary Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. We quantified subcutaneous and visceral fat in more than 10,000 women and men who also had genome-wide association data available. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, near the THNSL2 gene. These findings were not observed in men. We also interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed for 7 of these loci, most notably for VAT/SAT ratio. We conclude that genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not uncovered in large-scale GWAS of anthropometric traits.

Published
2012

4. Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

Author

Benjamin Voight, Amelie Bonnefond, Mark Caulfield, Guillaume Pare, Manal Abdelmalek, Eleftheria Zeggini, Jeffrey Schwimmer, Anna Gloyn, Michael Preuss, Åsa Johansson, LAURA CRISPONI, Eco De Geus, Michael Weedon, Jeanne Clark, Joyce Van Meurs, Torben Jørgensen, Kirsi Pietiläinen, Nicole Glazer, Jaakko Kaprio, Alan Shuldiner, Braxton Mitchell, Patricia Munroe, Ozren Polasek, Elisabeth Thiering, Carla Vogel, Jennie Hui, ROBERTO ELOSUA, Amanda Bennett, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Alexander Doney, Peter P Pramstaller, Christian Dina, Lambertus Kiemeney, Sophie Visvikis-Siest, ANGELO SCUTERI, Udo Seedorf, Vilmundur Gudnason, Peter Kraft, Aroon Hingorani, Michael Marmot, Dale Nyholt, Mika Kivimaki, Mary Feitosa, Danielle Posthuma, Claudia Langenberg, Stavroula Kanoni, Mika Kähönen, David Hillman, Lachlan Coin, Eric Brunner, Terho Lehtimäki, Man Li, John Beilby, Peter Visscher, Anette P Gjesing, James Pankow, Ruben Hernaez, Taina Lajunen, Katja Aben, Daniel Witte, Willem Ouwehand, Eleanor Wheeler, Peter Kovacs, Debbie A Lawlor, Kevin Jacobs, Jianjun Liu, Joseph Massaro, Hana Lango Allen, Inga Prokopenko, Rafn Benediktsson, Philippe Froguel, Soumya Raychaudhuri, Cornelia Van Duijn, Annette Peters, Nita Forouhi, Chiara Lanzani, Tonu Esko, Ko Willems van Dijk, Sadaf Farooqi, John Carr, Reedik Mägi, David Melzer, Gerard Waeber, Sutapa Mukherjee, Lyle John Palmer, Francois Pattou, Claes Ohlsson, Perry Elliott, André Scherag, Inke König, Stephen O'rahilly, Thomas Meitinger, Michael Goddard, Lina Zgaga, Robert Weyant, Paul Elliott, Robert Luben, Albert Vernon Smith, MANUELA UDA, Avan Aihie Sayer, Richard Bergman, Gonneke Willemsen, Cecilia Lindgren, Olle Melander, Igor Rudan, Maris Teder-Laving, Hugh Watkins, Ulrich John, Epidemiology, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C. I. (Beitragende*r), Hebebrand, Johannes (Beitragende*r), Functional Genomics, Biological Psychology, Neuroscience Campus Amsterdam - integrative Analysis & Modeling, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, McCarthy, Mark I, Apollo - University of Cambridge Repository, Medical Research Council (MRC), Speliotes, Ek, YERGES ARMSTRONG, Lm, Wu, J, Hernaez, R, Kim, Lj, Palmer, Cd, Gudnason, V, Eiriksdottir, G, Garcia, Me, Launer, Lj, Nalls, Ma, Clark, Jm, Mitchell, Bd, Shuldiner, Ar, Butler, Jl, Tomas, M, Hoffmann, U, Hwang, Sj, Massaro, Jm, O'Donnell, Cj, Sahani, Dv, Salomaa, V, Schadt, Ee, Schwartz, Sm, Siscovick, D, Nash, Crn, Manunta, Paolo, Giant, Consortium, Magic, Investigator, Voight, Bf, Carr, Jj, Feitosa, Mf, Harris, Tb, Fox, C, Smith, Av, Kao, Wh, Hirschhorn, Jn, Borecki, Ib, Gold, Consortium, Hjelt Institute (-2014), Department of Public Health, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Transplantation Laboratory, Genetic Epidemiology, O', Donnell, Cj, Giant, and Paolisso, Giuseppe

Subjects
Blood Glucose, Male, Netherlands Twin Register (NTR), Cancer Research, Medizin, Genome-wide association study, Hepatitis, Diabetes and Endocrinology/Obesity, Cohort Studies, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Lectins, Nonalcoholic fatty liver disease, 80 and over, Insulin, 2.1 Biological and endogenous factors, Aetiology, Tomography, Adaptor Proteins, Signal Transducing/genetics Adult Aged Aged, 80 and over Blood Glucose/analysis Case-Control Studies Chondroitin Sulfate Proteoglycans/genetics Cohort Studies Fatty Liver/*genetics/metabolism/radiography Genome-Wide Association Study Humans Insulin/blood Lectins, C-Type/genetics Lipase/genetics Male Membrane Proteins/genetics Middle Aged Mutation, Missense Nerve Tissue Proteins/genetics Polymorphism, Single Nucleotide Quantitative Trait Loci Tomography, X-Ray Computed, Genetics (clinical), Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Framingham Risk Score, C-Type, Liver Disease, Fatty liver, Adaptor Proteins, Single Nucleotide, Middle Aged, X-Ray Computed, 3. Good health, GOLD Consortium, 030211 gastroenterology & hepatology, Research Article, Adult, lcsh:QH426-470, Quantitative Trait Loci, Chronic Liver Disease and Cirrhosis, Mutation, Missense, genome-wide, fatty liver, metabolic, Nerve Tissue Proteins, Genetics and Genomics/Complex Traits, Biology, Polymorphism, Single Nucleotide, Gastroenterology and Hepatology/Hepatology, MAGIC Investigators, 03 medical and health sciences, Clinical Research, GIANT Consortium, medicine, Humans, Lectins, C-Type, Adiponutrin, NASH CRN, ddc:610, Polymorphism, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Adaptor Proteins, Signal Transducing, Aged, 030304 developmental biology, 0604 Genetics, Genetic heterogeneity, Prevention, Human Genome, Signal Transducing, Membrane Proteins, Lipase, medicine.disease, 3141 Health care science, Fatty Liver, lcsh:Genetics, Chondroitin Sulfate Proteoglycans, Case-Control Studies, Mutation, Missense, Steatosis, Steatohepatitis, Tomography, X-Ray Computed, Digestive Diseases, Neurocan, Genome-Wide Association Study, Developmental Biology
Abstract

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p, Author Summary NAFLD is a spectrum of disease that ranges from steatosis to steatohepatitis (nonalcoholic steatohepatitis or NASH: inflammation around the fat) to fibrosis/cirrhosis. Hepatic steatosis can be measured non-invasively using computed tomography (CT) whereas NASH/fibrosis is assessed histologically. The genetic underpinnings of NAFLD remain to be determined. Here we estimate that 26%–27% of the variation in CT measured hepatic steatosis is heritable or genetic. We identify three variants near PNPLAL3, NCAN, and PPP1R3B that associate with CT hepatic steatosis and show that variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B, associate with histologic lobular inflammation/fibrosis. Variants in or near NCAN, GCKR, and PPP1R3B associate with altered serum lipid levels, whereas those in or near LYPLAL1 and PNPLA3 do not. Variants near GCKR and PPP1R3B also affect glycemic traits. Thus, we show that NAFLD is genetically influenced and expand the number of common genetic variants that associate with this trait. Our findings suggest that development of hepatic steatosis, NASH/fibrosis, or abnormalities in metabolic traits are probably influenced by different metabolic pathways that may represent distinct therapeutic targets.

Published
2011

5. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

Author

Benjamin Voight, Amelie Bonnefond, Mark Caulfield, Jong-Young Lee, Ruth Loos, Nancy Heard-Costa, Eleftheria Zeggini, Cristiano FAVA, Anna Gloyn, Michael Preuss, Åsa Johansson, LAURA CRISPONI, Eco De Geus, Michael Weedon, Jeanne Clark, Francesco CUCCA, Marjo-Riitta Jarvelin, Torben Jørgensen, Andrea Maschio, Kirsi Pietiläinen, Nicole Glazer, Jaakko Kaprio, Valur Emilsson, Goncalo Abecasis, Andrew Taylor, Nicole Soranzo, Serena Sanna, Patricia Munroe, Ozren Polasek, Jan A. Staessen, Jennie Hui, Elina Hypponen, ROBERTO ELOSUA, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Bruce H.R. Wolffenbuttel, Alexander Doney, Peter P Pramstaller, Christian Dina, Lambertus Kiemeney, Sophie Visvikis-Siest, Mohammad Arfan Ikram, ANGELO SCUTERI, Udo Seedorf, Behrooz Ziad Alizadeh, John Whitfield, Vilmundur Gudnason, Maris Laan, Chris Wallace, Gavin Lucas, E Shyong Tai, Peter Kraft, Michael Marmot, Thor Aspelund, Dale Nyholt, Christian Gieger, Mika Kivimaki, Michael Sternberg, Lorena Citterio, Weiguo Zhang, Mary Feitosa, María Soler Artigas, Claudia Langenberg, Mika Ala-Korpela, Stavroula Kanoni, Uwe Völker, Mika Kähönen, Tomonori Okamura, Marcus Dörr, David Hillman, Lachlan Coin, Gideon Hirschfield, Eric Brunner, Maryam Kavousi, Terho Lehtimäki, Man Li, Carsten Oliver Schmidt, John Beilby, Peter Visscher, Sally Ricketts, Katja Aben, Halit Ongen, Christie Ballantyne, Adebowale Adeyemo, Fabio Marroni, Willem Ouwehand, Toby Johnson, Meena Kumari, Peter Kovacs, Debbie A Lawlor, Jianjun Liu, Grant Montgomery, Nicholas Martin, Francesco Mattace-Raso, Inga Prokopenko, Rafn Benediktsson, Margus Viigimaa, Peter Würtz, Philippe Froguel, Fadi Charchar, Soumya Raychaudhuri, Wolfram Goessling, Alena Yaluri, Cornelia Van Duijn, Timothy Frayling, Daniel Shriner, Nita Forouhi, Jana Van Vliet-Ostaptchouk, Bram Prins, Peter Whincup, David MASSON, Ronald Stolk, Ayse Demirkan, Janoš Terzić, James Pirruccello, Maciej Tomaszewski, Martin Tobin, Ko Willems van Dijk, John Carr, Elin Org, Reedik Mägi, Xiaofeng Zhu, Gerard Waeber, Koichi Matsuda, Winston Hide, Lyle John Palmer, Francois Pattou, Dorairaj Prabhakaran, Markus M. Lerch, Mark Wass, Claes Ohlsson, Paul O'Reilly, Vasiliki Lagou, Pedro Marques-Vidal, Sudha Seshadri, Tom Gaunt, Peter Wurz, Giriraj Ratan Chandak, Louise Wain, Antti Kangas, Matthijs Boekholdt, Niels Grarup, Jemma Hopewell, Thomas Meitinger, Lina Zgaga, Dag Steinar Thelle, Robert Weyant, Thomas Wang, Paul Elliott, Robert Luben, Albert Vernon Smith, Vinod Kumar, Pankaj Arora, MANUELA UDA, Daniel Gudbjartsson, Avan Aihie Sayer, Christa Meisinger, Kirsten Ohm Kyvik, Ming-Huei Chen, Susana Eyheramendy, Kenechi Ejebe, Stephen E Humphries, Ioanna Tzoulaki, Florian Kronenberg, Richard Bergman, Laura Zagato, Carlo Rivolta, NILUFER RAHMIOGLU, Vasan Ramachandran, Anna Dominiczak, Gonneke Willemsen, Mark McCarthy, Cecilia Lindgren, Olle Melander, Igor Rudan, Xueling Sim, Hugh Watkins, Edward Lakatta, Other departments, Experimental Vascular Medicine, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Chambers, John C, Zhang, Weihua, Sehmi, Joban, Li, Xiunzhong, Hypponen, Elina, Kooner, Jaspal S, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Faculteit Medische Wetenschappen/UMCG, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Psychiatry, NCA - Anxiety & Depression, NCA - Attention & Cognition, EMGO - Mental health, Epidemiology, Surgery, Gastroenterology & Hepatology, Pediatrics, Internal Medicine, and Ehret, Georg Benedikt

Subjects
Netherlands Twin Register (NTR), Candidate gene, Genome-wide association study, Liver disease, Delta-5 Fatty Acid Desaturase, 0302 clinical medicine, HEPATOCELLULAR-CARCINOMA, GENETIC-VARIANTS, METABOLIC SYNDROME, ddc:616, Genetics, 0303 health sciences, Glycobiology, GWAS, liver enzymes, COMMON VARIANTS, Genomics, Single Nucleotide, C-REACTIVE PROTEIN, Enzymes, 3. Good health, GWAS liver enzymes plasma, Blood, Liver, 030220 oncology & carcinogenesis, HEREDITARY CHOLESTASIS, SUSCEPTIBILITY LOCI, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Enzymes/blood/genetics, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, CORONARY-HEART-DISEASE, Polymorphism, Gene, 030304 developmental biology, Hormonal regulation [IGMD 6], Liver/enzymology, Lipid metabolism, medicine.disease, SALT EXPORT PUMP, RISK-FACTORS, Genome-Wide Association Study, Liver function
Abstract

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. Major support for the work came from European Commission (FP5, FP6 and FP7); European Science Foundation; European Science Council

Published
2011

6. Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes

Author

Eleftheria Zeggini, Anna Gloyn, Michael Weedon, Torben Jørgensen, Nicole Soranzo, Augustine Kong, Yurii Aulchenko, Andrew Hattersley, Christian Dina, Kerrin Small, Claudia Langenberg, Rafn Benediktsson, Philippe Froguel, Panos Deloukas, Cornelia Van Duijn, David Couper, Jana Van Vliet-Ostaptchouk, Winston Hide, Åsa Hedman, Krina Zondervan, Thomas Meitinger, Richard Bergman, Mark McCarthy, Cecilia Lindgren, and Igor Rudan

Subjects
Adipose Tissue/metabolism, Quantitative Trait Loci, Kruppel-Like Transcription Factors, Locus (genetics), Genome-wide association study, KLF14, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genomic Imprinting, 0302 clinical medicine, Genetics, Humans, ddc:576.5, Gene, 030304 developmental biology, Regulation of gene expression, Sp Transcription Factors, Sp Transcription Factors/genetics, 0303 health sciences, Cholesterol, HDL/genetics, Cholesterol, HDL, Phenotype, Adipose Tissue, Diabetes Mellitus, Type 2, Gene Expression Regulation, Expression quantitative trait loci, Diabetes Mellitus, Type 2/genetics, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associations been characterized. In parallel, whereas cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention. Here we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression. Expression levels of genes regulated by this trans-eQTL are highly correlated with concurrently measured metabolic traits, and a subset of the trans-regulated genes harbor variants directly associated with metabolic phenotypes. This trans-eQTL network provides a mechanistic understanding of the effect of the KLF14 locus on metabolic disease risk and offers a potential model for other complex traits. © 2011 Nature America, Inc. All rights reserved.

Published
2010

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