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1. Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

Author: John Michael Gaziano, Snehal Patil, Cassiane Robinson-Cohen, Thomas W. Winkler, Humaira Rasheed, Anna Köttgen, Christopher J. O'Donnell, Sarah E. Graham, Stein Hallan, Brett R Vanderweff, Kira J Stanzick, Cristian Pattaro, Matthias Wuttke, Bjørn Olav Åsvold, Iris M. Heid, Adriana M. Hung, Bryce X Rowan, Pascal Schlosser, Klaus Stark, VA Million Veteran Program, Cristen J. Willer, André Gessner, Yong Li, Mathias Gorski, and Laurent F. Thomas
Subjects: 0301 basic medicine, Science, Quantitative Trait Loci, 610 Medizin, General Physics and Astronomy, Renal function, Genome-wide association study, RNA-Seq, Computational biology, Biology, Quantitative trait locus, Kidney, Genome-wide association studies, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Chronic kidney disease, Genetics research, Databases, Genetic, medicine, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, Gene, Genetic association, ddc:610, Multidisciplinary, Kidney metabolism, General Chemistry, medicine.disease, Cystatins, Europe, 030104 developmental biology, Gene Expression Regulation, Organ Specificity, Creatinine, Single-Cell Analysis, Biomarkers, 030217 neurology & neurosurgery, Genome-Wide Association Study, Glomerular Filtration Rate, Kidney disease
Abstract: Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up., Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.
Published: 2021

2. An Asian-specific MPL genetic variant alters JAK–STAT signaling and influences platelet count in the population

Author: Santhi K. Ganesh, Yan Zhang, Karen Sl Lam, Haiyi Yu, Yujun Dong, Yong Huo, Min-Lee Yang, Wei Zhou, He Zhang, Cristen J. Willer, Hung Fat Tse, Y. Eugene Chen, Chloe Y Y Cheung, Wei Gao, Pak C. Sham, Clara S. Tang, Jia Jia, Ming Xu, Yi Fu, and Pengfei Sun
Subjects: Population, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Asian People, Genetics, medicine, Humans, SNP, Allele, Association Studies Article, education, Molecular Biology, Gene, Allele frequency, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Platelet Count, General Medicine, medicine.disease, Leukemia, Receptors, Thrombopoietin, Genome-Wide Association Study, Signal Transduction
Abstract: Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)–trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (β = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10−13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK–STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.
Published: 2021
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3. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Author: Nancy L. Heard-Costa, Lucas Barwick, Clary B. Clish, Celeste Eng, Joanne M. Murabito, Esteban G. Burchard, Yii-Der Ida Chen, Daniel I. Chasman, Robert C. Kaplan, James B. Meigs, Deborah A. Nickerson, Cashell E. Jaquish, Eric Boerwinkle, Jennifer A. Brody, Charles Kooperberg, Mark T. Gladwin, Sebastian Schoenherr, Keng-Han Lin, John Barnard, Ryan D. Hernandez, Andrew D. Johnson, Edwin K. Silverman, Mollie A. Minear, Michelle Daya, Barbara A. Konkle, Sharon R. Browning, Daniel E. Weeks, Wendy S. Post, Alexander P. Reiner, Kathryn L. Lunetta, Gina M. Peloso, David Van Den Berg, Dan E. Arking, Seung-been Lee, Leslie A. Lange, Cristen J. Willer, Zachary A. Szpiech, Tasha E. Fingerlin, Wayne E. Clarke, Xutong Zhao, Stephen S. Rich, Nora Franceschini, Sudha Seshadri, Chloé Sarnowski, Hyun Min Kang, Sayantan Das, Michael C. Zody, Stephanie M. Fullerton, Dean Bobo, Alanna C. Morrison, Brian Custer, Nona Sotoodehnia, Shannon Kelly, Thomas W. Blackwell, Bruce M. Psaty, Yingze Zhang, Susan R. Heckbert, Robert E. Gerszten, M. Benjamin Shoemaker, Daniel Taliun, Leslie S. Emery, André Corvelo, Michael H. Cho, Braxton D. Mitchell, Xiaoming Liu, Stella Aslibekyan, Paul L. Auer, Brandon Chalazan, Sarah C. Nelson, Seung Hoan Choi, Jeong-Sun Seo, Matthew P. Conomos, Anne-Katrin Emde, Lawrence F. Bielak, Alisa K. Manning, Allison E. Ashley-Koch, Diane Fatkin, Xiaowen Tian, Emelia J. Benjamin, D. C. Rao, Mina K. Chung, Myriam Fornage, Daniel Levy, Michael D. Kessler, Weihong Tang, Daniel J. Gottlieb, Pradeep Natarajan, Jessica Lasky-Su, Amol C. Shetty, Cathy C. Laurie, Dan M. Roden, Timothy D. O’Connor, Jedidiah Carlson, Lewis C. Becker, Achilleas N. Pitsillides, Karine A. Viaud-Martinez, Raul Torres, Adolfo Correa, Christian Fuchsberger, Deborah A. Meyers, Alvaro Alonso, Sanghamitra Mohanty, Jonathon LeFaive, Soren Germer, Julie L. Mikulla, François Aguet, Susan K. Dutcher, Sarah A Gagliano Taliun, Ani Manichaikul, Lori Garman, Xiuqing Guo, Timothy A. Thornton, David D. McManus, Albert V. Smith, Kristin G. Ardlie, Anna Köttgen, Sharon L.R. Kardia, Quenna Wong, Jill M. Johnsen, Andrea Natale, Richard A. Gibbs, Douglas P. Kiel, Ingo Ruczinski, Susan Redline, Lukas Forer, Scott I. Vrieze, May E. Montasser, Rasika A. Mathias, Jerome I. Rotter, Jacob Pleiness, Chunyu Liu, Brian L. Browning, James G. Wilson, Weiniu Gan, Christine M. Albert, Marilyn J. Telen, Courtney G. Montgomery, Steven A. Lubitz, Robert Klemmer, Ramachandran S. Vasan, Nathan Pankratz, Mariza de Andrade, Vivien A. Sheehan, Kenneth Rice, Xihong Lin, Eimear E. Kenny, Stephanie M. Gogarten, John Blangero, Donna K. Arnett, Jiang He, Pankaj Qasba, James F. Casella, Patrick T. Ellinor, Nicholette D. Palmer, R. Graham Barr, Scott T. Weiss, Joanne E. Curran, Bruce S. Weir, Kari E. North, L. Adrienne Cupples, Dawn L. DeMeo, Tanika N. Kelly, Angel C.Y. Mak, Russell P. Tracy, David A. Schwartz, Kent D. Taylor, Rebecca L. Beer, Daniel N. Harris, George J. Papanicolaou, Marguerite R. Irvin, Stephen T. McGarvey, Sebastian Zöllner, Patricia A. Peyser, Brian E. Cade, Ruth J. F. Loos, Douglas Loesch, Nicholas L. Smith, Gonçalo R. Abecasis, Jennifer A. Smith, Michael E. Hall, Lu-Chen Weng, Jeffrey R. O'Connell, Adrienne M. Stilp, Donald W. Bowden, Kathleen C. Barnes, Stacey Gabriel, Michael Boehnke, Wayne Huey-Herng Sheu, and Dawood Darbar
Subjects: Quality Control, Heterozygote, Genomics, Computational biology, Biology, Polymorphism, Single Nucleotide, Genome, Article, DNA sequencing, INDEL Mutation, Loss of Function Mutation, Genetics research, Genetic variation, Humans, Precision Medicine, Genetic association, Population Density, Multidisciplinary, Whole Genome Sequencing, Genome, Human, Genetic Variation, Rare variants, United States, Genetic architecture, Phenotype, Cytochrome P-450 CYP2D6, Haplotypes, Mutagenesis, Sample Size, Next-generation sequencing, National Heart, Lung, and Blood Institute (U.S.), Imputation (genetics), Reference genome
Abstract: The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%., The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.
Published: 2021
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4. Exome sequencing and characterization of 49,960 individuals in the UK Biobank

Author: David J. Carey, Cristen J. Willer, Anthony Marcketta, Claudia Schurmann, Leland Barnard, John Penn, Suganthi Balasubramanian, Daren Liu, Joseph B. Leader, Gonçalo R. Abecasis, Marcus B. Jones, John C. Whittaker, Ashutosh K. Pandey, Ida Surakka, David H. Ledbetter, Evan Maxwell, John D. Overton, Andrew Blumenfeld, Michael N. Cantor, Robert A. Scott, Wendy K. Chung, Alexander H. Li, Alexander Lopez, Joshua D. Backman, Matthew R. Nelson, Jeffrey Staples, Giovanni Coppola, Jonathan Marchini, Xiaodong Bai, Kavita Praveen, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, Aris N. Economides, Shareef Khalid, William J Salerno, Bin Ye, Cristopher V. Van Hout, Kristian Hveem, Jeffrey G. Reid, Colm O'Dushlaine, Joshua D. Hoffman, Laura M. Yerges-Armstrong, Nilanjana Banerjee, Sean O'Keeffe, Ioanna Tachmazidou, Lon R. Cardon, Alicia Hawes, Aris Baras, Ashish Yadav, George D. Yancopoulos, and Lukas Habegger
Subjects: Male, 0301 basic medicine, Genes, BRCA2, Genes, BRCA1, Hasso-Plattner-Institut für Digital Engineering GmbH, Penetrance, 030204 cardiovascular system & hematology, Ion Channels, 0302 clinical medicine, Bone Density, Loss of Function Mutation, Neoplasms, Databases, Genetic, Genetics research, Genotype, Exome, Exome sequencing, Biological Specimen Banks, education.field_of_study, Multidisciplinary, Genomics, Middle Aged, Biobank, Pedigree, Phenotype, ras GTPase-Activating Proteins, Female, Kidney Diseases, Population, Collagen Type VI, Computational biology, Biology, Article, DNA sequencing, Varicose Veins, 03 medical and health sciences, Exome Sequencing, Humans, education, Alleles, Aged, Demography, Rare variants, Peptide Fragments, United Kingdom, 030104 developmental biology, ddc:000, Next-generation sequencing
Abstract: The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community., Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
Published: 2020
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5. Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses

Author: Yoonsu Cho, Ben Michael Brumpton, Jaakko Kaprio, Johan Håkon Bjørngaard, Elliot M. Tucker-Drob, Tim T Morris, Neil M Davies, Sean Harrison, Laurence J. Howe, Wei-Min Chen, Nancy L. Pedersen, Gunnhild Åberge Vie, Kristian Hveem, Karl Heilbron, Fernando Pires Hartwig, Michel G. Nivard, Gibran Hemani, Laura D Howe, George Davey Smith, David M. Evans, Michael C. Neale, Bjørn Olav Åsvold, Eleanor Sanderson, Adam Auton, Andrew D. Grotzinger, Shuai Li, Amanda Hughes, Cristen J. Willer, Chandra A. Reynolds, Frank Windmeijer, Dorret I. Boomsma, John L. Hopper, Alexandra Havdahl, Institute for Molecular Medicine Finland, Department of Public Health, University of Helsinki, HUS Helsinki and Uusimaa Hospital District, APH - Methodology, APH - Mental Health, Biological Psychology, Brumpton, Ben [0000-0002-3058-1059], Sanderson, Eleanor [0000-0001-5188-5775], Hartwig, Fernando Pires [0000-0003-3729-0710], Harrison, Sean [0000-0002-7966-0700], Vie, Gunnhild Åberge [0000-0003-1552-5291], Cho, Yoonsu [0000-0001-6118-6652], Havdahl, Alexandra [0000-0002-9268-0423], Neale, Michael [0000-0003-4887-659X], Nivard, Michel G [0000-0003-2015-1888], Grotzinger, Andrew [0000-0001-7852-9244], Morris, Tim [0000-0001-8178-6815], Willer, Cristen [0000-0001-5645-4966], Evans, David M [0000-0003-0663-4621], Kaprio, Jaakko [0000-0002-3716-2455], Davey Smith, George [0000-0002-1407-8314], Hemani, Gibran [0000-0003-0920-1055], Davies, Neil M [0000-0002-2460-0508], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), gene-environment correlation, Epidemiology, General Physics and Astronomy, Matematikk og Naturvitenskap: 400::Basale biofag: 470 [VDP], Body Mass Index, 0302 clinical medicine, HEIGHT, Risk Factors, Genetics research, genetics, 030212 general & internal medicine, lcsh:Science, Multidisciplinary, Confounding, Mendelian Randomization Analysis, ASSOCIATION, 3142 Public health care science, environmental and occupational health, educational attainment, Female, TRAITS, TRANSMISSION, Science, Biology, Population stratification, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, BMI, 03 medical and health sciences, Medical research, SDG 3 - Good Health and Well-being, Mendelian randomization, Genetics, LINKAGE, Humans, Matematikk og Naturvitenskap: 400 [VDP], COMMON, Linkage (software), EDUCATIONAL-ATTAINMENT, Assortative mating, Gene-environment correlation, General Chemistry, confounding, BODY-MASS INDEX, 3141 Health care science, 030104 developmental biology, Matematikk og Naturvitenskap: 400::Basale biofag: 470::Genetikk og genomikk: 474 [VDP], INFERENCE, lcsh:Q, DISEQUILIBRIUM, Body mass index, height, Demography
Abstract: Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies., Family-based study designs have been applied to resolve confounding by population stratification, dynastic effects and assortative mating in genetic association analyses. Here, Brumpton et al. describe theory and simulations for overcoming such biases in Mendelian randomization through within-family studies.
Published: 2020
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6. A Novel Variant in APOB Gene Causes Extremely Low LDL-C Without Known Adverse Effects

Author: Robert D. Brook, Whitney E. Hornsby, Melvyn Rubenfire, Richard L. Weinberg, Cristen J. Willer, Kristian Hveem, Lars G. Fritsche, Y. Eugene Chen, Linda Farhat, and Ida Surakka
Subjects: 0301 basic medicine, medicine.medical_specialty, Apolipoprotein B, Apob gene, Low density lipoprotein cholesterol, Case Report, 030105 genetics & heredity, apolipoprotein B loss-of-function, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Clinical Case, Internal medicine, medicine, Diseases of the circulatory (Cardiovascular) system, FHBL, familial hypobetalipoproteinemia, Adverse effect, Lipoprotein cholesterol, low-density lipoprotein cholesterol, apoB, apolipoprotein B, biology, business.industry, hypobetalipoproteinemia, medicine.disease, Endocrinology, RC666-701, LoF, loss-of-function, biology.protein, lipids (amino acids, peptides, and proteins), LDL-C, low-density lipoprotein cholesterol, Hypobetalipoproteinemia, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: A novel frameshift variant was identified in APOB that segregates in a dominant manner with low levels of low-density lipoprotein cholesterol. Affected family members show no apparent clinical complications. There is no consensus regarding clinical management, and the long-term consequences of low levels of low-density lipoprotein cholesterol remain unknown. (Level of Difficulty: Advanced.), Graphical abstract, A novel frameshift variant was identified in APOB that segregates in a dominant manner with low levels of low-density lipoprotein cholesterol…
Published: 2020

7. Global Biobank Meta-analysis Initiative: powering genetic discovery across human diseases

Author: Sarah Finer, Yen-Feng Lin, Michigan Genomics Initiative, Valeria Lo Faro, Benjamin M. Neale, Nathan Ingold, Estonian Biobank, Peter Straub, Jasmina Uzunovic, Triin Laisk, Whitney E. Hornsby, Sebastian Zoellner, Takahiro Konuma, Jordan A. Shavit, Masahiro Kanai, Xue Zhong, Stephen J. Wicks, Taiwan Biobank, Arjun Bhattacharya, Nicholas J. Douville, Yi Ding, BioVU, Jennifer E. Huffman, Christopher R. Gignoux, Kristian Hveem, Serena Sanna, Brooke N. Wolford, Mitja I. Kurki, Aarno Palotie, Yukinori Okada, FinnGen, Clara Lajonchere, Ida Surakka, Mass General Brigham Biobank, Jie Zheng, Caroline Hayward, Riccardo E. Marioni, Chris Griffiths, Lars G. Fritsche, Rasheed Humaira, Ben Michael Brumpton, Kristi Läll, Kuang Lin, Jordan W. Smoller, Lude Franke, Michelle Daya, David C. Whiteman, Karen A. Hunt, Harold Snieder, Jun Lv, Stuart MacGregor, Alicia R. Martin, Juha Karjalainen, Jonathan A. Shortt, Kuan-Han H. Wu, Jibril B Hirbo, Sameer Chavan, Marie-Julie Favé, Snehal Patil, Kristy Crooks, Sarah E. Graham, Tzu-Ting Chen, Michael Preuss, Matthew Zawistowski, Yen-Chen Anne Feng, Iona Y Millwood, Cisca Wijmenga, Cristen J. Willer, Jansonius Nomdo, Kristin Tsuo, Qimr Berghofer Biobank, Koichi Matsuda, LifeLines, Shinichi Namba, Nicholas M. Rafaels, Priit Palta, Unnur Thorsteinsdottir, Chia-Yen Chen, Generation Scotland, Cecilia M. Lindgren, Huiling Zhao, Andrea Ganna, Bogdan Pasaniuc, Maasha Mutaamba, Nancy J. Cox, Zhengming Chen, George Davey Smith, Mark J. Daly, Sarah E. Medland, Yu Guo, Daniel H. Geschwind, Matthew Law, Judith M. Vonk, Eimear E. Kenny, David J. Porteous, Tian Ge, Judy H. Cho, UK Biobank, Ruth J. F. Loos, Eric R. Gamazon, Wei Zhou, Richard C. Trembath, Philip Awadalla, Kathleen C. Barnes, David A. van Heel, Kari Stefansson, Archie Campbell, Hilary C. Martin, Tom R. Gaunt, Ruth E. Johnson, Sinéad B. Chapman, Esteban A Lopera-Maya, Michael Boehnke, Brett Vanderwerff, Catherine M. Olsen, Marike Boezen, Anita Pandit, BioMe, Ran Tao, Hilary K. Finucane, Anne Richmond, Ying Wang, Liming Li, Geertruida H. de Bock, John Wright, Xiang Zhou, Robin G. Walters, Reedik Mägi, and Hailiang Huang
Subjects: Disease gene, 0303 health sciences, South asia, Collaborative network, Genome-wide association study, Computational biology, Biology, Biobank, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Baseline characteristics, Meta-analysis, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: SummaryBiobanks are being established across the world to understand the genetic, environmental, and epidemiological basis of human diseases with the goal of better prevention and treatments. Genome-wide association studies (GWAS) have been very successful at mapping genomic loci for a wide range of human diseases and traits, but in general, lack appropriate representation of diverse ancestries - with most biobanks and preceding GWAS studies composed of individuals of European ancestries. Here, we introduce the Global Biobank Meta-analysis Initiative (GBMI) -- a collaborative network of 19 biobanks from 4 continents representing more than 2.1 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWAS generated using harmonized genotypes and phenotypes from member biobanks. GBMI brings together results from GWAS analysis across 6 main ancestry groups: approximately 33,000 of African ancestry either from Africa or from admixed-ancestry diaspora (AFR), 18,000 admixed American (AMR), 31,000 Central and South Asian (CSA), 341,000 East Asian (EAS), 1.4 million European (EUR), and 1,600 Middle Eastern (MID) individuals. In this flagship project, we generated GWASs from across 14 exemplar diseases and endpoints, including both common and less prevalent diseases that were previously understudied. Using the genetic association results, we validate that GWASs conducted in biobanks worldwide can be successfully integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics between biobanks. We demonstrate the value of this collaborative effort to improve GWAS power for diseases, increase representation, benefit understudied diseases, and improve risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of the studied traits.
Published: 2021
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8. The causal effects of serum lipids and apolipoproteins on kidney function: multivariable and bidirectional Mendelian-randomization analyses

Author: Ole-Jørgen Bekkevold, Stein Hallan, Jie Zheng, George Davey Smith, Solfrid Romundstad, Maiken Elvestad Gabrielsen, Bjørn Olav Åsvold, Ben Michael Brumpton, Humaira Rasheed, Kristian Hveem, Laurent F. Thomas, Jessica M. B. Rees, Tom G. Richardson, Si Fang, Tom R. Gaunt, Eleanor Sanderson, Anne Heidi Skogholt, Cristen J. Willer, Stephen Burgess, Endre Bakken Stovner, Rees, Jessica [0000-0002-1495-2470], Sanderson, Eleanor [0000-0001-5188-5775], Richardson, Tom G [0000-0002-7918-2040], Brumpton, Ben [0000-0002-3058-1059], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, medicine.medical_specialty, kidney, Apolipoprotein B, Epidemiology, Blood lipids, Renal function, 030204 cardiovascular system & hematology, lipids, 03 medical and health sciences, chemistry.chemical_compound, Random Allocation, 0302 clinical medicine, Internal medicine, urinary albumin-to-creatinine ratio, Mendelian randomization, medicine, eGFR, Humans, AcademicSubjects/MED00860, Triglycerides, urinary albumen to creatinine ratio, Creatinine, biology, Triglyceride, business.industry, Mendelian Randomization Analysis, General Medicine, Lipids, 030104 developmental biology, Endocrinology, Apolipoproteins, chemistry, Cystatin C, biology.protein, lipids (amino acids, peptides, and proteins), business, apolipoproteins, Genome-Wide Association Study
Abstract: Background The causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear. Methods Using two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). We obtained lipid- and apolipoprotein-associated genetic variants from the Global Lipids Genetics Consortium (n = 331 368) and UK Biobank (n = 441 016), respectively, and kidney-function markers from the Trøndelag Health Study (HUNT; n = 69 736) and UK Biobank (n = 464 207). The reverse causal direction was examined using variants associated with kidney-function markers selected from recent genome-wide association studies. Results There were no strong associations between genetically predicted lipid and apolipoprotein levels with kidney-function markers. Some, but inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by low-density lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. For high-density lipoprotein cholesterol (HDL-C), results differed between eGFRcrea and eGFRcys, but neither analysis suggested substantial effects. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels. Conclusion Our MR estimates suggest that serum lipid and apolipoprotein levels do not cause substantial changes in kidney function. A possible weak effect of higher atherogenic lipids on increased eGFR and UACR warrants further investigation. Processes leading to higher UACR may lead to more atherogenic lipid levels.
Published: 2021
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9. Genome-wide association study of cardiac troponin i in the general population

Author: Ida Surakka, Magnus Nakrem Lyngbakken, Nay Aung, Jonathon LeFaive, Caroline Hayward, Ailin Falkmo Hansen, Wei Zhou, Paul Welsh, Sarah E. Graham, Jonas B. Nielsen, Sarah A Gagliano Taliun, Archie Campbell, Brooke N. Wolford, Patricia B. Munroe, David J. Porteous, Bjørn Olav Åsvold, Marta R Moksnes, Lars G. Fritsche, George Davey Smith, Cristen J. Willer, Torbjørn Omland, Humaira Rasheed, Nicholas J. Douville, Ben Michael Brumpton, Helge Røsjø, Kristian Hveem, Laurent F. Thomas, Anne Richmond, Naveed Sattar, and Steffen E. Petersen
Subjects: AcademicSubjects/SCI01140, medicine.medical_specialty, Heart disease, Population, Quantitative Trait Loci, Gene Expression, Genome-wide association study, macromolecular substances, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, Troponin T, Internal medicine, Mendelian randomization, Troponin I, Genetics, medicine, genetics, Myocardial infarction, cardiovascular diseases, education, Association Studies Article, genes, Molecular Biology, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, education.field_of_study, genome-wide association study, cardiac troponin i, Chromosome Mapping, Genetic Variation, General Medicine, Mendelian Randomization Analysis, medicine.disease, musculoskeletal system, Genetics, Population, Organ Specificity, Heart failure, Cardiology, cardiovascular system, Biomarker (medicine), Biomarkers, Genome-Wide Association Study
Abstract: Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.
Published: 2021
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10. Type 2 diabetes sex-specific effects associated with E167K coding variant in TM6SF2

Author: Anubha Mahajan, Kezhong Zhang, Jun Song, Dongshan Yang, Zhipeng Liu, Jinjian Sun, Yanbo Fan, Y. Eugene Chen, Jifeng Zhang, Sarah E. Graham, Kristian Hveem, Ida Surakka, Wenying Liang, Haocheng Lu, Minerva T. Garcia-Barrio, Hyunbae Kim, Oren Rom, Brooke N. Wolford, Lars G. Fritsche, Maiken Elvestad Gabrielsen, Jonas B. Nielsen, Wei Zhou, Wanqing Liu, Shweta Ramdas, and Cristen J. Willer
Subjects: medicine.medical_specialty, Multidisciplinary, Physiology, Science, Type 2 diabetes, Diabetology, Genomics, Carbohydrate metabolism, Biology, medicine.disease, Transmembrane protein, Article, Impaired glucose tolerance, Endocrinology, Diabetes mellitus, Internal medicine, Nonalcoholic fatty liver disease, Unfolded protein response, medicine, Molecular physiology, TM6SF2
Abstract: Summary The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene (TM6SF2) is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the TM6SF2 rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts. The E167K variant was significantly associated with T2D, especially in males. Using an E167K knockin (KI) mouse model, we found that male but not the female KI mice exhibited impaired glucose tolerance. As an ER membrane protein, TM6SF2 was found to interact with inositol-requiring enzyme 1 α (IRE1α), a primary ER stress sensor. The male Tm6sf2 KI mice exhibited impaired IRE1α signaling in the liver. In conclusion, the E167K variant of TM6SF2 is associated with glucose intolerance primarily in males, both in humans and mice., Graphical abstract, Highlights • The TM6SF2 E167K variant is significantly associated with T2D, primarily in males • Male, but not female, Tm6sf2 KI mice exhibited impaired glucose tolerance • IRE1α signaling is attenuated in the liver of male Tm6sf2 KI mice • IDE and LIPIN1 were dysregulated in the liver of male KI mice but not the females, Physiology; Molecular physiology; Diabetology; Genomics
Published: 2021

11. Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Author: Akhil Pampana, Xiuqing Guo, Tanika N. Kelly, Yii-Der Ida Chen, Charles Kooperberg, Chii-Min Hwu, Mariaelisa Graff, Jiang He, Xihao Li, Patrick T. Ellinor, Joshua C. Bis, Kari E. North, Nancy L. Heard-Costa, Joseph Park, Stacey Gabriel, Joanne E. Curran, Braxton D. Mitchell, Lee-Ming Chuang, Ravindranath Duggirala, Jerome I. Rotter, Robert C. Kaplan, Soren Germer, Pradeep Natarajan, Take Naseri, Xihong Lin, Susan K. Dutcher, Stella Aslibekyan, Ryan W. Kim, Daniel J. Rader, Richard A. Gibbs, Myriam Fornage, Eric Boerwinkle, Bertha Hidalgo, Muagututi’a S. Reupena, Deborah A. Nickerson, Zhe Wang, Donald W. Bowden, Yuxuan Wang, Alanna C. Morrison, Stephen S. Rich, David Zhang, Gina M. Peloso, Xiaohui Li, Martin Lisa, Lisa de las Fuentes, Zilin Li, Alexander P. Reiner, Jennifer A. Brody, Lisa R. Yanek, Marguerite R. Irvin, Bruce M. Psaty, Bao Wei, Preuss Michael, Leslie A. Lange, John T. Wilkins, Russell P. Tracy, Paul S. de Vries, Wei Zhao, Rasika A. Mathias, Susan Redline, Xiao Sun, Kent D. Taylor, Barry I. Freedman, Ani Manichaikul, Donna K. Arnett, Nicholette D. Palmer, Cristen J. Willer, Steven A. Lubitz, Sharon L.R. Kardia, L. Adrienne Cupples, Ramachandran S. Vasan, May E. Montasser, Ren-Hua Chung, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, Ruth J. F. Loos, Jennifer A. Smith, John Blangero, Brian G. Kral, Karine A. Viaud Martinez, Stephen T. McGarvey, Adolfo Correa, Michael Y. Tsai, Patricia A. Peyser, and Brian E. Cade
Subjects: Genetics, Whole genome sequencing, Genome Scan, Blood lipids, Biology, medicine.disease, Genome, symbols.namesake, Mendelian inheritance, symbols, medicine, lipids (amino acids, peptides, and proteins), Allele, Gene, Dyslipidemia
Abstract: Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and interpretation of potential clinical significance. Increasingly larger whole genome sequence datasets with plasma lipids coupled with methodologic advances enable us to more fully catalog the allelic spectrum for lipids. Here, among 66,329 ancestrally diverse (56% non-European ancestry) participants, we associate 428M variants from deep-coverage whole genome sequences with plasma lipids. Approximately 400M of these variants were not studied in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with plasma lipids through analysis of common and rare coding variants. We additionally discover several significantly associated rare non-coding variants largely at Mendelian lipid genes. Notably, we detect rareLDLRintronic variants associated with markedly increased LDL-C, similar to rareLDLRexonic variants. In conclusion, we conducted a systematic whole genome scan for plasma lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
Published: 2021
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12. Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

Author: Ailin Falkmo Hansen, Amy M. Mason, Ketil Thorstensen, Sarah E. Graham, Kristian Hveem, Cristen J. Willer, Dipender Gill, Ben Michael Brumpton, Bjørn Olav Åsvold, Sarah A Gagliano Taliun, Jonas B. Nielsen, David Schlessinger, Lars G. Fritsche, Francesco Cucca, Stephen Burgess, Marta R Moksnes, Kuan-Han Wu, Wei Zhou, and Gonçalo R. Abecasis
Subjects: Genetics, chemistry.chemical_classification, medicine.diagnostic_test, Transferrin saturation, Iron deficiency, Biology, medicine.disease, chemistry, Total iron-binding capacity, Transferrin, Mendelian randomization, medicine, Serum iron, Biomarker (medicine), Genetic association
Abstract: Iron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron binding capacity) in the Trøndelag Health Study (HUNT), the Michigan Genomics Initiative (MGI) and the SardiNIA study, followed by their meta-analysis with publicly available summary statistics, analyzing up to 257 953 individuals. We identify 127 genetic loci associated with iron traits. Among 19 novel protein-altering variants, we observe a rare missense variant (rs367731784) in HUNT, which suggests a role for DNAJC13 in transferrin recycling. We further validate the latest genetic risk scores for each biomarker in HUNT (6% variance in serum iron explained) and present linear and non-linear Mendelian randomization analyses of the traits on all-cause mortality. We find evidence of a harmful effect of increased serum iron and transferrin saturation in linear analyses that estimate population-averaged effects. However, there was weak evidence of a protective effect of increasing serum iron at the very low end of its distribution. Our findings contribute to our understanding of the genes affecting iron status and its consequences on human health.
Published: 2021
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13. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease

Author: Steinunn Thordardottir, Kristian Hveem, Per Selnes, Silke Kern, Wei Zhou, Srdjan Djurovic, Iris E. Jansen, Ole A. Andreassen, Petroula Proitsi, Linda M. Pedersen, Tormod Fladby, Tore Wergeland Meisingset, Chandra A. Reynolds, Angela Hodges, Ingmar Skoog, Alexey A. Shadrin, Bendik S. Winsvold, Margda Waern, Geir Bråthen, Danielle Posthuma, Lavinia Athanasiu, Richard Dobson, Adam Auton, Shahram Bahrami, Anna Zettergren, Maiken Elvestad Gabrielsen, Henrik Zetterberg, Eystein Stordal, Geir Selbæk, John-Anker Zwart, Laurent F. Thomas, Amy E Martinsen, Ingun Ulstein, Jonas B. Nielsen, Kari Stefansson, Ole Kristian Drange, Arvid Rongve, Anne Heidi Skogholt, Julia M. Sealock, Sigrid Botne Sando, Palmi V. Jonsson, Jon Snaedal, Kaj Blennow, Ingvild Saltvedt, Lars G. Fritsche, Karl Heilbron, Jeanne E. Savage, Sigurdur H. Magnusson, Ingunn Bosnes, Stephan Ripke, Marianne Bakke Johnsen, Ida K. Karlsson, Lea K. Davis, Latha Velayudhan, Nancy L. Pedersen, Dag Aarsland, Cristen J. Willer, Hreinn Stefansson, Dominic Holland, Sigrid Børte, Douglas P Wightman, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, and Complex Trait Genetics
Subjects: Genetics, Microglia, Polygenic disease, Genome-wide association study, Disease, Biology, medicine.disease, Article, medicine.anatomical_structure, Immune system, SDG 3 - Good Health and Well-being, Polymorphism (computer science), medicine, Dementia, Gene
Abstract: Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.
Published: 2021
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14. Incorporating family disease history and controlling case-control imbalance for population based genetic association studies

Author: Wei Zhou, Kisung Nam, Seunggeun Lee, Wenjian Bi, Bhramar Mukherjee, Yongwen Zhuang, Cristen J. Willer, and Brooke N. Wolford
Subjects: Mixed model, education.field_of_study, medicine.medical_specialty, Calibration (statistics), Population, Biology, Biobank, Correlation, Statistics, Epidemiology, medicine, education, Genetic association, Type I and type II errors
Abstract: In the genome-wide association analysis of population-based biobanks, most diseases have low prevalence, which results in low detection power. One approach to tackle the problem is using family disease history, yet existing methods are unable to address type I error inflation induced by increased correlation of phenotypes among closely related samples, as well as unbalanced phenotypic distribution. We propose a new method for genetic association test with family disease history, TAPE (mixed-model-based Test with Adjusted Phenotype and Empirical saddlepoint approximation), which controls for increased phenotype correlation by adopting a two-variance-component mixed model, accounts for case-control imbalance by using empirical saddlepoint approximation, and is flexible to incorporate any existing adjusted phenotypes such as phenotypes from the LT-FH method. We show through simulation studies and analysis of UK-Biobank data of white British samples and the Korean Genome and Epidemiology Study (KoGES) of Korean samples that the proposed method is robust and yields better calibration compared to existing methods while gaining power for detection of variant-phenotype associations.
Published: 2021
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15. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

Author: Helgadottir A, Giannakopoulou O, Costanzo Mc, Heribert Schunkert, Giardoglou P, Markus M. Nöthen, Zhou W, Thomas Meitinger, Deepak Atri, Murgia F, Amit Khera, Tao Jiang, Munz M, Jeanette Erdmann, Patrick T. Ellinor, Marju Orho-Melander, Rajat M. Gupta, Kazuyoshi Ishigaki, Satoshi Koyama, Güldener U, Dongkeun Jang, Hilary K. Finucane, George Hindy, George Dedoussis, Cristen J. Willer, Johan L.M. Björkegren, Aris Baras, Marc S. Sabatine, Flannick J, Arno Ruusalepp, Alanna C. Morrison, Danesh J, Christopher P. Nelson, Nicholas A Marston, Thorgeirsson G, Ida Surakka, Sherliker P, Kastrati A, Ibrahim M, Ito K, Robert Clarke, Christopher Grace, Minxian Wang, Boerwinkle E, Haider Smi, Anuj Goel, Ben Michael Brumpton, Lijiang Ma, Sekar Kathiresan, Li L, Pang S, Carolina Roselli, Issei Komuro, de Vries Ps, Kristian Hveem, Hilma Holm, Adam S. Butterworth, Lotta La, Panagiotis Deloukas, Unnur Thorsteinsdottir, Thorsten Kessler, Kamanu Fk, Roberts R, Arnar Do, Tom R. Webb, Ulirsch Jk, Jonas B. Nielsen, Reinberger T, Martin Farrall, Daniel F. Gudbjartsson, Elle M. Weeks, Kari Stefansson, Brooke N. Wolford, Krishna G. Aragam, Hugh Watkins, von Scheidt M, Yoichiro Kamatani, Pierre Zalloua, Christian T. Ruff, Muñoz Venegas L, Iftikhar J. Kullo, Gudmar Thorleifsson, Stavroula Kanoni, Olle Melander, Nilesh J. Samani, Michael R. Brown, Loukianos S. Rallidis, Jemma C. Hopewell, and Mucha S
Subjects: Coronary artery disease, Pathogenesis, medicine, CAD, Genome-wide association study, Vascular proliferation, Computational biology, Biology, Disease pathogenesis, medicine.disease, Gene
Abstract: Rapid progress of the discovery of genetic loci associated with common, complex diseases has outpaced the elucidation of mechanisms pertinent to disease pathogenesis. To address relevant barriers for coronary artery disease (CAD), we combined genetic discovery analyses with downstream characterization of likely causal variants, genes, and biological pathways. Specifically, we conducted a genome-wide association study (GWAS) comprising 181,522 cases of CAD among 1,165,690 participants. We detected 241 associations, including 54 associations and 30 loci not previously linked to CAD. Next, we prioritized likely causal variants using functionally-informed fine-mapping, yielding 42 associations with fewer than five variants in the 95% credible set. Combining eight complementary predictors, we prioritized 185 candidate causal genes, including 94 genes supported by three or more predictors. Similarity-based clustering underscored a role for early developmental processes, cell cycle signaling, and vascular proliferation in the pathogenesis of CAD. Our analysis identifies and systematically characterizes risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
Published: 2021
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16. Exploring and visualizing large-scale genetic associations by using PheWeb

Author: Ryan P. Welch, Ellen M. Schmidt, Jonas B. Nielsen, Peter VandeHaar, Cristen J. Willer, Andrew P. Boughton, Gonçalo R. Abecasis, Daniel Taliun, Wei Zhou, Lars G. Fritsche, Michael Boehnke, Seunggeun Lee, and Sarah A Gagliano Taliun
Subjects: Scale (ratio), business.industry, Extramural, Data Visualization, MEDLINE, Genome-wide association study, Computational biology, Biology, Polymorphism, Single Nucleotide, Article, User-Computer Interface, Data visualization, Urinary Bladder Neoplasms, Genetics, Humans, business, Software, Genome-Wide Association Study
Published: 2020
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17. Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis

Author: Oliver Husser, J. Gustav Smith, Costanza Pellegrini, Viktor Lazovic, Christopher P. Nelson, Lingyao Zeng, Wolfgang Koenig, Kristian Hveem, Adnan Kastrati, Colin N. A. Palmer, Heribert Schunkert, Jesper R. Gådin, Peter S. Braund, Teresa Trenkwalder, Ify R. Mordi, Chim C. Lang, Christian Hengstenberg, Per Eriksson, Radoslaw Debiec, Jonas B. Nielsen, Sarah E. Graham, Thorsten Kessler, Amparo Aracil, Andreas Martinsson, Nilesh J. Samani, Anders Franco-Cereceda, Muntaser D. Musameh, Cristen J. Willer, and Tobias Rheude
Subjects: Male, medicine.medical_specialty, Coronary Artery Disease, 030204 cardiovascular system & hematology, Lower risk, Polymorphism, Single Nucleotide, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Allele, Aged, biology, business.industry, valvular heart disease, Case-control study, Genetic Variation, Aortic Valve Stenosis, Lipoprotein(a), Middle Aged, medicine.disease, Stenosis, Genetic Loci, Case-Control Studies, Aortic valve stenosis, biology.protein, Cardiology, Female, Chromosomes, Human, Pair 9, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract: Background Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. Methods We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. Results In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24–1.52, p = 6.9 × 10−10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31–1.79) compared to those with CAD (OR 1.27; 95%CI 1.12–1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88–0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27–1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95–1.02). Conclusions Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.
Published: 2019
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18. Variants associated with HHIP expression have sex-differential effects on lung function

Author: Carl A. Melbourne, Caroline Hayward, Stefan Karrasch, Dirk Keidel, Katherine A. Fawcett, Susan M. Ring, Yohan Bossé, Carol A. Wang, Ben Michael Brumpton, Claudia Langenberg, Peter K. Joshi, Ke Hao, Igor Rudan, David J. Porteous, Don D. Sin, Raquel Granell, Blair H. Smith, Jian'an Luan, Kristian Hveem, Sarah E. Harris, Sandosh Padmanabhan, Archie Campbell, Sebastian May-Wilson, Veronique Vitart, Nicola Pirastu, Arnulf Langhammer, Craig E. Pennell, John M. Starr, Stefan Weiss, Karina Patasova, Nicholas J. Wareham, James F. Wilson, Deborah Jarvis, Tim D. Spector, Nick Shrine, David P. Strachan, Martin D. Tobin, Beate Stubbe, David M. Evans, Kirsi H. Pietiläinen, Mangino Massimo, Ian P. Hall, Graham L. Hall, Jaakko Kaprio, Ralf Ewert, Rachel E. Foong, Claudia Flexeder, Louise V. Wain, Ma'en Obeidat, Cristen J. Willer, Leo-Pekka Lyytikäinen, Olli T. Raitakari, John Henderson, Konstantin Strauch, Marta R Moksnes, Cosetta Minelli, Nicole Probst-Hensch, Pirro G. Hysi, Anna L. Guyatt, Henry Völzke, Thomas Meitinger, Peter D. Sly, Ozren Polasek, Anne Richmond, Mika Kähönen, Maarten van den Berge, Medea Imboden, Thibaud Boutin, Lucija Klaric, Laura Portas, Terho Lehtimäki, Ian J. Deary, Taina Rantanen, Catherine John, Teemu Palviainen, Fawcett, Katherine A [0000-0002-6675-2112], Obeidat, Ma'en [0000-0002-5443-2752], Shrine, Nick [0000-0003-3641-4371], Weiss, Stefan [0000-0002-3553-4315], May-Wilson, Sebastian [0000-0003-2668-5717], Boutin, Thibaud S [0000-0003-4754-1675], Portas, Laura [0000-0003-1789-1893], Harris, Sarah E [0000-0002-4941-5106], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Palviainen, Teemu [0000-0002-7847-8384], Keidel, Dirk [0000-0003-4706-5728], Minelli, Cosetta [0000-0001-9166-3958], Langenberg, Claudia [0000-0002-5017-7344], Bossé, Yohan [0000-0002-3067-3711], Van den Berge, Maarten [0000-0002-9336-7340], Sin, Don D [0000-0002-0756-6643], Campbell, Archie [0000-0003-0198-5078], Porteous, David [0000-0003-1249-6106], Padmanabhan, Sandosh [0000-0003-3869-5808], Smith, Blair H [0000-0002-5362-9430], Ring, Sue [0000-0003-3103-9330], Rantanen, Taina [0000-0002-1604-1945], Pennell, Craig E [0000-0002-0937-6165], Kaprio, Jaakko [0000-0002-3716-2455], Vitart, Veronique [0000-0002-4991-3797], Hayward, Caroline [0000-0002-9405-9550], Hall, Ian P [0000-0001-9933-3216], Wain, Louise V [0000-0003-4951-1867], Apollo - University of Cambridge Repository, Groningen Research Institute for Asthma and COPD (GRIAC), Technology Centre, University of Helsinki, Institute for Molecular Medicine Finland, Genetic Epidemiology, HUS Abdominal Center, Department of Medicine, Clinicum, CAMM - Research Program for Clinical and Molecular Metabolism, Department of Public Health, Research Programs Unit, Tampere University, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, and Department of Clinical Physiology and Nuclear Medicine
Subjects: 0301 basic medicine, Spirometry, medicine.medical_specialty, HHIP, Medicine (miscellaneous), Expression, Genome-wide Interaction Study, Hhip, Lung Function, Sex, Single-nucleotide polymorphism, Biology, 3121 Internal medicine, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Genome-wide interaction study, Lung function, Internal medicine, expression, medicine, sex, Allele, Enhancer, Gene, Lung, genome-wide interaction study, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, lung function, ALSPAC, Differential effects, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, 030228 respiratory system, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P-8) interactions with sex on lung function, and 21 showed suggestive interactions (P-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
Published: 2021
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19. Within-sibship GWAS improve estimates of direct genetic effects

Author: Ailin Falkmo Hansen, Christina C. Dahm, David M. Evans, Massimo Mangino, Melissa C. Southey, Lawrence F. Bielak, Ben Michael Brumpton, Sharon L.R. Kardia, Archie Campbell, Yoonsu Cho, Tim T Morris, Patrick Turley, Jeffrey S. Reid, Laurence J. Howe, Kaare Christensen, Karri Silventoinen, Sudheer Giddaluru, John K. Hewitt, Philipp Koellinger, W. David Hill, Daniel J. Benjamin, Gibran Hemani, Margaret J. Wright, Scott D. Gordon, Elliot M. Tucker-Drob, Rosa Cheesman, Nicholas G. Martin, Robin G. Walters, Paraskevi Christofidou, Aris Baras, George Davey Smith, Matthew C. Keller, John D. Overton, Deepika R Dokuru, Jennifer A. Smith, Nancy L. Pedersen, Michel G. Nivard, Dorret I. Boomsma, Jaakko Kaprio, Humaira Rasheed, Hyeokmoon Kweon, Sara Hägg, Shona M. Kerr, John L. Hopper, Pekka Martikainen, Teemu Palviainen, Luke M. Evans, Patricia A. Peyser, Jared V. Balbona, Lucija Klaric, Tim D. Spector, Patrik K. E. Magnusson, Melinda Mills, Alexandra Havdahl, Chandra A. Reynolds, Jean-Baptiste Pingault, Zhengming Chen, Shuai Li, Harry Campbell, Travis T. Mallard, Cristen J. Willer, Yunzhang Wang, Yongkang Kim, Robert Plomin, Marianne Nygaard, Michael C. Stallings, Sarah E. Medland, Anne E. Justice, Geetha Chittoor, Debbie A Lawlor, Øyvind Næss, Liming Li, Kuang Lin, Eco J. C. de Geus, Christopher R. Bauer, Matthijs D. van der Zee, Iona Y Millwood, Caroline Hayward, Penelope A. Lind, David J. Porteous, K. Paige Harden, Meike Bartels, Neil M Davies, James F. Wilson, Bjørn Olav Åsvold, Antti Latvala, Scott M. Ratliff, and Kristian Hveem
Subjects: 0303 health sciences, education.field_of_study, Assortative mating, Population, Genome-wide association study, Biology, Population stratification, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Genetic variation, Mendelian randomization, Human height, education, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: Estimates from genome-wide association studies (GWAS) represent a combination of the effect of inherited genetic variation (direct effects), demography (population stratification, assortative mating) and genetic nurture from relatives (indirect genetic effects). GWAS using family-based designs can control for demography and indirect genetic effects, but large-scale family datasets have been lacking. We combined data on 159,701 siblings from 17 cohorts to generate population (between-family) and within-sibship (within-family) estimates of genome-wide genetic associations for 25 phenotypes. We demonstrate that existing GWAS associations for height, educational attainment, smoking, depressive symptoms, age at first birth and cognitive ability overestimate direct effects. We show that estimates of SNP-heritability, genetic correlations and Mendelian randomization involving these phenotypes substantially differ when calculated using within-sibship estimates. For example, genetic correlations between educational attainment and height largely disappear. In contrast, analyses of most clinical phenotypes (e.g. LDL-cholesterol) were generally consistent between population and within-sibship models. We also report compelling evidence of polygenic adaptation on taller human height using within-sibship data. Large-scale family datasets provide new opportunities to quantify direct effects of genetic variation on human traits and diseases.
Published: 2021
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20. Rare coding variants in 35 genes associate with circulating lipid levels – a multi-ancestry analysis of 170,000 exomes

Author: Marju Orho-Melander, Humberto García-Ortiz, Xueling Sim, Amp-T D-Genes, Cheol Joo Park, Gina M. Peloso, Jason Flannick, Brian Tomlinson, Hyun Min Kang, Emilio J. Cordova, Stephen S. Rich, Richard A. Gibbs, Angélica Martínez-Hernández, Lorena Orozco, Harsha Doddapaneni, Lisa R. Yanek, Jiwon Lee, Namrata Gupta, Valeriya Lyssenko, Sohee Han, James B. Meigs, Bong-Jo Kim, Bruce M. Psaty, Leslie S. Emery, Kerrin S. Small, Pradeep Natarajan, May E. Montasser, Christian Gieger, Sharon L.R. Kardia, Sarah C. Nelson, Craig L. Hanis, Heikki A. Koistinen, María Elena González-Villalpando, Edmund Chan, Michael Y. Tsai, Benjamin Glaser, Thomas Meitinger, Matthew J. Bown, Mariaelisa Graff, John Danesh, Sekar Kathiresan, Tiinamaija Tuomi, Ramachandran S. Vasan, Gil Atzmon, Alyna T. Khan, Diego Ardissino, Yii-Der Ida Chen, David Zhang, Rob M. van Dam, Wendy S. Post, Barry I. Freedman, D. C. Rao, Michael Preuss, Donna M. Lehman, L. Adrienne Cupples, Colin N. A. Palmer, Claudia H. T. Tam, Hortensia Moreno-Macías, Markku Laakso, Peter Dornbos, Teresa Tusié-Luna, Stella Aslibekyan, Marguerite R. Irvin, Daniel J. Rader, Jee-Young Moon, Eimear E. Kenny, Lisa W. Martin, Jennifer A. Brody, Amit Khera, Erwin P. Bottinger, Sarah E. Graham, Myriam Fornage, Ruth McPherson, Nancy L. Heard-Costa, Michael Boehnke, Clicerio Gonzalez, Ryan W. Kim, Yi-Cheng Chang, Peter M. Nilsson, Yik Ying Teo, Robert Sladek, Cristen J. Willer, Fei Fei Wang, Donna K. Arnett, Mark Chaffin, Karine A. Viaud Martinez, Alanna C. Morrison, Leslie A. Lange, Ravindranath Duggirala, Donna M. Muzny, Kent D. Taylor, Niels Grarup, Soren Germer, Patricia A. Peyser, Brian E. Cade, Lewis C. Becker, Steven A. Lubitz, Nicholette D. Palmer, Susan K. Dutcher, Ronald C.W. Ma, Xuenan Mi, Xiuqing Guo, Hugh Watkins, Eric Boerwinkle, Qibin Qi, Johanna Kuusisto, Christie M. Ballantyne, Tanika N. Kelly, Rajiv Chowdhury, Elvia Mendoza-Caamal, Wing-Yee So, Tien Yin Wong, Torben Hansen, Cecilia Contreras-Cubas, Jeong-Sun Seo, Mi Yeong Hwang, Daekwan Seo, Dajiang J. Liu, Cristina Revilla-Monsalve, Paul S. de Vries, Daniel R. Witte, Yi-Jen Hung, Olle Melander, Karen L. Mohlke, Lucinda Antonacci-Fulton, Francisco Barajas-Olmos, Soo Heon Kwak, Daniel E. Weeks, Claudia Schurmann, Ginger A. Metcalf, Young-Jin Kim, Adrienne M. Stilp, Lori L. Bonnycastle, John Blangero, Ralph A. DeFronzo, Donald W. Bowden, Rasika A. Mathias, Oluf Pedersen, Rozenn N. Lemaitre, Stephen T. McGarvey, Heribert Schunkert, Jaakko Tuomilehto, Farook Thameem, Valentin Fuster, Joshua C. Bis, George Hindy, Allan Linneberg, James G. Wilson, Kyong Soo Park, Sergio A. Islas-Andrade, Ching-Yu Cheng, Won Jung Choi, Minxian X. Wang, Xuzhi Wang, Adolfo Correa, Jai G. Broome, Gail P. Jarvik, Alexander P. Reiner, E. Shyong Tai, Juyoung Lee, Mark I. McCarthy, Nilesh J. Samani, Susan Redline, Carlos A. Aguilar-Salinas, Jerome I. Rotter, Ma. Eugenia Garay-Sevilla, Jiang He, Patrick T. Ellinor, Joseph Park, Joanne E. Curran, Nir Barzilai, Federico Centeno-Cruz, Seonwook Lee, Lawrence F. Bielak, Jianjun Liu, Charles Kooperberg, Juan M. Peralta, Jose C. Florez, Leif Groop, Noël P. Burtt, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, and Ruth J. F. Loos
Subjects: Genetics, 0303 health sciences, education.field_of_study, Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, DNA sequencing, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, SNP, education, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
Published: 2020
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21. Largest GWAS (N=1,126,563) of Alzheimer’s Disease Implicates Microglia and Immune Cells

Author: Tore Wergeland Meisingset, Kari Stefansson, Shahram Bahrami, Sigurdur H. Magnusson, Tormod Fladby, Ingunn Bosnes, Lavinia Athanasiu, Danielle Posthuma, Sigrid Botne Sando, Stephan Ripke, Linda M. Pedersen, Amy E Martinsen, Dag Aarsland, Ole Kristian Drange, Henrik Zetterberg, Alexey A. Shadrin, Margda Waern, Steinunn Thordardottir, Sigrid Børte, Wei Zhou, Kristian Hveem, Marianne Bakke Johnsen, Julia M. Sealock, Eystein Stordal, Geir Selbæk, Silke Kern, John-Anker Zwart, Iris E. Jansen, Palmi V. Jonsson, Ole A. Andreassen, Ingvild Saltvedt, Ingmar Skoog, Maiken Elvestad Gabrielsen, Cristen J. Willer, Chandra A. Reynolds, Ingun Ulstein, Arvid Rongve, Anne Heidi Skogholt, Douglas P Wightman, Richard Dobson, Anna Zettergren, Lea K. Davis, Nancy L. Pedersen, Ida K. Karlsson, Srdjan Djurovic, Kaj Blennow, Laurent F. Thomas, Latha Velayudhan, Angela Hodges, Bendik S. Winsvold, Jon Snaedal, Lars G. Fritsche, Hreinn Stefansson, Petra Proitsi, Jeanne E. Savage, Jonas B. Nielsen, and Geir Bråthen
Subjects: Genetics, medicine.anatomical_structure, Immune system, Drug development, Amyloid, Microglia, medicine, Dementia, Genome-wide association study, Disease, Biology, medicine.disease, Gene
Abstract: SummaryLate-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases1. Late-onset Alzheimer’s disease is caused by a combination of many genetic variants with small effect sizes and environmental influences. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified2,3. Here we show that increased sample sizes allowed for identification of seven novel genetic loci contributing to Alzheimer’s disease. We highlighted eight potentially causal genes where gene expression changes are likely to explain the association. Human microglia were found as the only cell type where the gene expression pattern was significantly associated with the Alzheimer’s disease association signal. Gene set analysis identified four independent pathways for associated variants to influence disease pathology. Our results support the importance of microglia, amyloid and tau aggregation, and immune response in Alzheimer’s disease. We anticipate that through collaboration the results from this study can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants which contribute to Alzheimer’s pathology. Furthermore, the increased understanding of the mechanisms that mediate the effect of genetic variants on disease progression will help identify potential pathways and gene-sets as targets for drug development.
Published: 2020
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22. Use of a Polygenic Risk Score Improves Prediction of Myocardial Injury After Non-Cardiac Surgery

Author: Whitney E. Hornsby, Christopher Douville, Aleda Leis, Ida Surakka, Milo Engoren, Sachin Kheterpal, Cristen J. Willer, Nicholas J. Douville, Chad M. Brummett, and Michael R. Mathis
Subjects: Adult, Male, medicine.medical_specialty, Genotype, Myocardial Infarction, Coronary Artery Disease, 030204 cardiovascular system & hematology, Article, Coronary artery disease, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Risk Factors, 030202 anesthesiology, Internal medicine, Odds Ratio, medicine, Humans, Myocardial infarction, Retrospective Studies, biology, business.industry, General Medicine, Middle Aged, medicine.disease, Precision medicine, Troponin, Logistic Models, ROC Curve, Area Under Curve, Non cardiac surgery, Cardiology, biology.protein, Female, Polygenic risk score, business
Abstract: Background: While postoperative myocardial injury remains a major driver of morbidity and mortality, the ability to accurately identify patients at risk remains limited despite decades of clinical research. The role of genetic information in predicting myocardial injury after noncardiac surgery (MINS) remains unknown and requires large scale electronic health record and genomic data sets. Methods: In this retrospective observational study of adult patients undergoing noncardiac surgery, we defined MINS as new troponin elevation within 30 days following surgery. To determine the incremental value of polygenic risk score (PRS) for coronary artery disease, we added the score to 3 models of MINS risk: revised cardiac risk index, a model comprised entirely of preoperative variables, and a model with combined preoperative plus intraoperative variables. We assessed performance without and with PRSs via area under the receiver operating characteristic curve and net reclassification index. Results: Among 90 053 procedures across 40 498 genotyped individuals, we observed 429 cases with MINS (0.5%). PRS for coronary artery disease was independently associated with MINS for each multivariable model created (odds ratio=1.12 [95% CI, 1.02–1.24], P =0.023 in the revised cardiac risk index-based model; odds ratio, 1.19 [95% CI, 1.07–1.31], P =0.001 in the preoperative model; and odds ratio, 1.17 [95% CI, 1.06–1.30], P =0.003 in the preoperative plus intraoperative model). The addition of clinical risk factors improved model discrimination. When PRS was included with preoperative and preoperative plus intraoperative models, up to 3.6% of procedures were shifted into a new outcome classification. Conclusions: The addition of a PRS does not significantly improve discrimination but remains independently associated with MINS and improves goodness of fit. As genetic analysis becomes more common, clinicians will have an opportunity to use polygenic risk to predict perioperative complications. Further studies are necessary to determine if PRSs can inform MINS surveillance.
Published: 2020
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23. Genome-scale CRISPR screening for modifiers of cellular LDL uptake

Author: David Ginsburg, Emily J. Sherman, Sarah E. Graham, Cristen J. Willer, Brian T. Emmer, and Paul J. Lascuna
Subjects: chemistry.chemical_classification, Cell type, chemistry, Transferrin, LDL receptor, Regulator, CRISPR, lipids (amino acids, peptides, and proteins), Guide RNA, Biology, Endocytosis, Gene, Cell biology
Abstract: Hypercholesterolemia is a causal and modifiable risk factor for atherosclerotic cardiovascular disease. A critical pathway regulating cholesterol homeostasis involves the receptor-mediated endocytosis of low-density lipoproteins into hepatocytes, mediated by the LDL receptor. We applied genome-scale CRISPR screening to query the genetic determinants of cellular LDL uptake in HuH7 cells cultured under either lipoprotein-rich or lipoprotein-starved conditions. Candidate LDL uptake regulators were validated through the synthesis and secondary screening of a customized library of gRNA at greater depth of coverage. This secondary screen yielded significantly improved performance relative to the primary genome-wide screen, with better discrimination of internal positive controls, no identification of negative controls, and improved concordance between screen hits at both the gene and gRNA level. We then applied our customized gRNA library to orthogonal screens that tested for the specificity of each candidate regulator for LDL versus transferrin endocytosis, the presence or absence of genetic epistasis with LDLR deletion, the impact of each perturbation on LDLR expression and trafficking, and the generalizability of LDL uptake modifiers across multiple cell types. These findings identified several previously unrecognized genes with putative roles in LDL uptake and suggest mechanisms for their functional interaction with LDLR.
Published: 2020
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24. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

Author: Jeffrey R. O'Connell, James A. Perry, Mark Chaffin, Cotton Seed, Maris Alver, L. Adrienne Cupples, May E. Montasser, Jesse M. Engreitz, Seyedeh M. Zekavat, Stephen S. Rich, W. Craig Johnson, Adolfo Correa, Sekar Kathiresan, Benjamin M. Neale, Andrea Ganna, James G. Wilson, Ramachandran S. Vasan, Braxton D. Mitchell, Wei Zhao, Gina M. Peloso, Amit Khera, Gonçalo R. Abecasis, Jason Ernst, Cristen J. Willer, Eric S. Lander, Ida Surakka, Veikko Salomaa, Pradeep Natarajan, Ani Manichaikul, Jonathan M. Bloom, Timothy Poterba, Manolis Kellis, Tõnu Esko, Samuli Ripatti, Jerome I. Rotter, Sanni Ruotsalainen, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Centre of Excellence in Complex Disease Genetics, Clinicum, Doctoral Programme in Population Health, Biostatistics Helsinki, and Complex Disease Genetics
Subjects: 0301 basic medicine, PREDICTION, POLYGENIC RISK SCORES, EFFICIENT, General Physics and Astronomy, Blood lipids, Genome-wide association study, Cardiovascular, Genome, chemistry.chemical_compound, 0302 clinical medicine, Gene Frequency, Models, GENETIC-VARIANTS, Genotype, WIDE ASSOCIATION, 2.1 Biological and endogenous factors, Aetiology, FAMILIAL HYPERCHOLESTEROLEMIA, lcsh:Science, GENERAL-POPULATION, Genetics, 0303 health sciences, Multidisciplinary, High-Throughput Nucleotide Sequencing, Lipids, NHLBI TOPMed Lipids Working Group, 3. Good health, Cholesterol, symbols, LOW-FREQUENCY, lipids (amino acids, peptides, and proteins), Human, Biotechnology, Science, Genomics, Locus (genetics), Quantitative trait locus, Biology, General Biochemistry, Genetics and Molecular Biology, Article, LDL, 03 medical and health sciences, symbols.namesake, Genetic, medicine, Humans, Gene, 030304 developmental biology, Whole genome sequencing, Models, Genetic, Base Sequence, Genome, Human, Human Genome, General Chemistry, Cholesterol, LDL, DIVERSE POPULATIONS, medicine.disease, Atherosclerosis, 030104 developmental biology, chemistry, Mutation, Mendelian inheritance, lcsh:Q, 3111 Biomedicine, RARE-VARIANT ASSOCIATION, Digestive Diseases, 030217 neurology & neurosurgery, Imputation (genetics), Dyslipidemia, Genome-Wide Association Study
Abstract: Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia., Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.
Published: 2018
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25. Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Author: Cashell E. Jaquish, Craig P. Hersh, Emily Barron-Casella, Larry Phillips, James S. Pankow, JoAnn E. Manson, Mariza de Andrade, Vivien A. Sheehan, Norann A. Zaghloul, Yongmei Liu, Sergei Nekhai, Russell P. Tracy, Bruce S. Weir, Pankaj Qasba, Adrienne M. Stilp, Tasha E. Fingerlin, Heather M. Ochs-Balcom, L. Adrienne Cupples, Rongze Yang, David A. Schwartz, Shannon Kelly, Scott E. Devine, Tanja Smith, G.L. Kinney, Beverly Snively, Kent D. Taylor, Manolis Kellis, Ruth J. F. Loos, Seth A. Ament, Kathleen C. Barnes, Robert C. Kaplan, Ulrich Broeckel, Hemant K. Tiwari, Karin F. Hoth, Peter Durda, Julie L. Mikulla, Charles B. Eaton, Cotton Seed, Merry Lynn McDonald, Eric Boerwinkle, Josh Smith, Honghuang Lin, Ingrid B. Borecki, Jeffrey L. Curtis, Emelia J. Benjamin, Kenneth Rice, Sharon L.R. Kardia, Nicholas L. Smith, Coleen M. Damcott, Jeffrey Haessler, Kimberly L. Jones, Elaine Cornell, Nona Sotoodehnia, Adolfo Correa, Rich Johnston, C. Charles Gu, Chii Min Hwu, Peter C. Anderson, Lesley F. Tinker, Colleen Davis, R. Graham Barr, Scott T. Weiss, Leanna Farnam, Chao Hsiung, Brian Silver, Patrick F. McArdle, Lisa W. Martin, Yii-Der Ida Chen, John Barnard, Holly Kramer, Sekar Kathiresan, Gonçalo R. Abecasis, Barry Make, Michael C. Mahaney, Marco V Perez, Donna K. Arnett, Mark Chaffin, Xiuqing Guo, Joshua C. Bis, Pamela Russell, Paul L. Auer, James G. Wilson, Marilyn J. Telen, David K. Levine, Jennifer A. Smith, Christopher Scheller, Meher Preethi Boorgula, Aakrosh Ratan, Kari E. North, Dan E. Arking, Elizabeth A. Regan, Margaret G. Parker, Andres Metspalu, Jai G. Broome, Daniel Taliun, Lynette Ekunwe, Alyna T. Khan, Hao Mei, Dhananjay Vaidya, Ellen M. Schmidt, Stanford Mwasongwe, Joshua P. Lewis, Stacey Gabriel, Christine E. Seidman, Margery Gass, Deborah A. Nickerson, Nicola L. Hawley, Rebecca L. Beer, Afshin Parsa, Steven L. Salzberg, Terri H. Beaty, Stella Aslibekyan, Girish N. Nadkarni, Wei Zhao, David L. Tirschwell, Karen Bunting, Dawn L. DeMeo, Laura J. Rasmussen-Torvik, Julia Powers Becker, Dmitry Prokopenko, Karen Schwander, Bruce D. Gelb, Stephanie Krauter, Laura M. Raffield, Michael E. Hall, Frank C. Sciurba, Lauren Margolin, Nora Franceschini, Daniel N. Harris, Seyedeh M. Zekavat, Dawood Darbar, Keng-Han Lin, Haley Huston, Steven A. Lubitz, Andrea Ganna, Carole Sztalryd, Cathy C. Laurie, Christy Chang, James E. Hixson, Steven A. McCarroll, Barbara A. Konkle, Michael D. Kessler, Scott I. Vrieze, Yingze Zhang, Sarah Ruuska, George J. Papanicolaou, Weiniu Gan, Maris Alver, Elizabeth A. Streeten, Fei Fei Wang, Lu-Chen Weng, Braxton D. Mitchell, Lee-Ming Chuang, Sean P. David, Wei-Min Chen, Susan R. Heckbert, Ryan D. Hernandez, Andrew D. Johnson, Cristen J. Willer, Ani Manichaikul, Jonathan M. Bloom, Timothy D. O’Connor, Sylvia Smoller, Marguerite R. Irvin, Seung Hoan Choi, Ida Surakka, Veikko Salomaa, Diane M. Becker, Ron Do, W. Craig Johnson, Cecelia A. Laurie, Meryl S. LeBoff, Aniket Shetty, Tõnu Esko, Michael C. Zody, Xiaoqi Geng, Da Wei Gong, Snow Xueyan Zhao, Esteban G. Burchard, Xiuwen Zheng, Cara L. Carty, Alexander P. Reiner, Tim Assimes, Deborah A. Meyers, Mina K. Chung, Harald H H Göring, Benjamin M. Neale, Pradeep Natarajan, Yan Gao, Stephen S. Rich, Yun Ju Sung, Susan K. Dutcher, Ferdouse Begum, Stephanie M. Gogarten, John Blangero, Jonathan Cardwell, Kayleen Williams, Rakhi P. Naik, Amol C. Shetty, Sayantan Das, Myriam Fornage, May E. Montasser, Michelle Daya, Edwin K. Silverman, Daniel E. Weeks, Laura J. Kaufman, Dimitrios Avramopoulos, Michael Y. Tsai, Christine M. Albert, Vijay G. Sankaran, Jeffrey R. O'Connell, Thomas W. Blackwell, Stephen T. McGarvey, Robert M. Reed, Leslie A. Lange, Qing Duan, Bruce M. Psaty, Leslie S. Emery, Bertha Hidalgo, Jennifer A. Brody, L. Keoki Williams, Soren Germer, Zhaohui S. Qin, Deepti Jain, Deborah Applebaum-Bowden, Carla Wilson, Degui Zhi, Christoph Lange, Elliott Hong, L.F. Bielak, Wen Jane Lee, Yue Guan, Tarik Walker, Rebecca D. Jackson, Charles R. Farber, Mark J. Daly, Stephanie M. Fullerton, John E. Hokanson, Karol E. Watson, James Luo, Richard Casaburi, Seunggeun Lee, Jill M. Johnsen, Margaret A. Taub, Ryan L. Minster, Ravi Duggirala, Susan K. Mathai, Yun Li, Quenna Wong, Matthew Flickinger, Huichun Xu, Susan Redline, Ulrike Peters, Ivana V. Yang, Jesse M. Engreitz, Sanni Ruotsalainen, Sean K. McFarland, Avram D Walts, Patricia A. Peyser, Allison E. Ashley-Koch, Lewis C. Becker, Nicholette Palmer Allred, James A. Perry, Jody S. Sylvia, Tamar Sofer, Vasan S. Ramachandran, Laura Almasy, Matthew J. Budoff, Ranjan Deka, David M. Herrington, Simeon I. Taylor, Daniel Levy, Chaojie Yang, Sameer Chavan, Kathleen A. Ryan, Josyf C. Mychaleckyj, Ingo Ruczinski, Sebastian Zoellner, Michael Preuss, Tim Poterba, Wendy S. Post, Amber L. Beitelshees, Ben Heavner, Carolina Roselli, Namiko Abe, Jonathon LeFaive, Mark T. Gladwin, Brian Custer, Robert B. Wallace, Simin Liu, Michael H. Cho, Robert E. Handsaker, Dabeeru C. Rao, Bo Juen Chen, Wayne Hui Heng Sheu, Xiang Zhou, Marcos Bezerra, Solomon K. Musani, Eimear E. Kenny, James F. Casella, Kathryn L. Lunetta, Nancy Min, Nicholas Rafaels, Lisa R. Yanek, Min A. Jhun, David C. Glahn, Rasika A. Mathias, Mollie A. Minear, Russell P. Bowler, Jason Ernst, Carolyn J. Crandall, Sara Penchev, Alvaro Alonso, Timothy A. Thornton, Toni I. Pollin, Charles Kooperberg, Ethan M. Lange, Juan M. Peralta, Pramod Anugu, Lucinda Fulton, Adam A. Szpiro, Michael R. DeBaun, M. Benjamin Shoemaker, Sam Phillips, Dan M. Roden, Mao Fu, Daniel I. Chasman, James D. Crapo, Hua Tang, Gina M. Peloso, Hyun Min Kang, Samuli Ripatti, Phuwanat Sakornsakolpat, Christopher R. Gignoux, Peter VandeHaar, Jerome I. Rotter, Dandi Qiao, Emily S. Wan, Shabnam Salimi, Kevin Sandow, Jiang He, Patrick T. Ellinor, Joanne E. Curran, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Clinicum, Doctoral Programme in Population Health, Department of Public Health, and Complex Disease Genetics
Subjects: 0301 basic medicine, Apolipoprotein B, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Lipoprotein particle, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, Aetiology, lcsh:Science, African Continental Ancestry Group, Genetics, Multidisciplinary, Genome, biology, CHOLESTEROL, Adaptor Proteins, Lipoprotein(a), Single Nucleotide, NHLBI TOPMed Lipids Working Group, 3142 Public health care science, environmental and occupational health, 3. Good health, Cholesterol, Heart Disease, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, RARE VARIANTS, lipids (amino acids, peptides, and proteins), LOW-FREQUENCY, Human, DNA Copy Number Variations, Science, Quantitative Trait Loci, European Continental Ancestry Group, Black People, POPULATION-SCALE, Quantitative trait locus, Article, White People, General Biochemistry, Genetics and Molecular Biology, LDL, Structural variation, 03 medical and health sciences, COMPONENTS-ANALYSIS, RISK-FACTOR, Humans, CORONARY-HEART-DISEASE, Polymorphism, Whole Genome Sequencing, Prevention, Human Genome, General Chemistry, Atherosclerosis, Vesicular Transport, Good Health and Well Being, 030104 developmental biology, chemistry, biology.protein, lcsh:Q, 3111 Biomedicine, Lipoprotein, Genome-Wide Association Study
Abstract: Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.
Published: 2018
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26. A novel homozygous ABCA1 variant in an asymptomatic man with profound hypoalphalipoproteinemia

Author: Robert D. Brook, Linda Farhat, Yaser Carcora, Melvyn Rubenfire, Daniel Seung Kim, and Cristen J. Willer
Subjects: Adult, Male, 0301 basic medicine, Endocrinology, Diabetes and Metabolism, Mutation, Missense, 030204 cardiovascular system & hematology, Asymptomatic, Cornea, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Tangier disease, Internal Medicine, Humans, Medicine, Hypoalphalipoproteinemia, Gene, Tangier Disease, Nutrition and Dietetics, biology, business.industry, Genetic heterogeneity, Cholesterol, HDL, Homozygote, Genetic disorder, Cholesterol, LDL, medicine.disease, 030104 developmental biology, ABCA1, Immunology, biology.protein, medicine.symptom, Cardiology and Cardiovascular Medicine, business, ATP Binding Cassette Transporter 1
Abstract: Low high-density lipoprotein cholesterol (HDL-C) can be caused by several acquired secondary causes as well as primary genetic disorders. However, only a few conditions are associated with profoundly reduced levels below 10 mg/dL. We present an unusual case of a healthy man with severely decreased HDL-C because of a novel homozygous variant causing a Proline > Arginine amino acid change at position 1412 in the ATP-binding cassette transporter A1 gene. Homozygous variations in ATP-binding cassette transporter A1 typically cause Tangier disease, a rare autosomal recessive condition linked with several other abnormalities (eg, enlarged discolored tonsils). Despite having an HDL-C below 10 mg/dL, our patient presented without any other clinical symptoms or physical signs suggestive of Tangier disease. This case of presumptive Tangier disease adds support to the growing body of evidence that this genetic disorder may have greater phenotypic heterogeneity along with a more varied presentation than traditionally considered.
Published: 2018
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27. Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Author: Unnur Thorsteinsdottir, Sridharan Rajamani, Páll Melsted, Erna V. Ivarsdottir, Jonas B. Nielsen, Jon Thor Sverrisson, David O Arnar, Maja-Lisa Løchen, Cristen J. Willer, Atli S Valgardsson, Oddgeir L. Holmen, Terje R. Pedersen, Daniel F. Gudbjartsson, Vinicius Tragante, Olafur B. Davidsson, Gardar Sveinbjornsson, Hilma Holm, Gisli H. Halldorsson, Ingileif Jonsdottir, Patrick Sulem, Marc S. Sabatine, Bjarni Torfason, Anna Helgadottir, Stefan Jonsson, Bjarni V. Halldorsson, Dan M. Roden, Solveig Gretarsdottir, Kristian Hveem, Gudmundur L. Norddahl, Ragnar P. Kristjansson, Folkert W. Asselbergs, Rosa B. Thorolfsdottir, Kari Stefansson, Gudmar Thorleifsson, and Dawood Darbar
Subjects: 0301 basic medicine, Medicine (miscellaneous), Genome-wide association study, 030204 cardiovascular system & hematology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Journal Article, Missense mutation, splice, Gene, lcsh:QH301-705.5, Sequence (medicine), Genetic association, Genetics, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Atrial fibrillation, medicine.disease, Exon skipping, 3. Good health, 030104 developmental biology, lcsh:Biology (General), VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, General Agricultural and Biological Sciences
Abstract: Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
Published: 2018
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28. Electronic health records: the next wave of complex disease genetics

Author: Cristen J. Willer, Brooke N. Wolford, and Ida Surakka
Subjects: 0301 basic medicine, Genotype, Quantitative Trait Loci, Population, Complex disease, Genome-wide association study, Health records, Biology, Polymorphism, Single Nucleotide, Field (computer science), 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, Genetics, Electronic Health Records, Humans, Invited Reviews, education, Molecular Biology, Genetics (clinical), Genetic association, education.field_of_study, Genetic Diseases, Inborn, Genetic data, General Medicine, Cloud Computing, Biobank, Genetics, Population, 030104 developmental biology, Cardiovascular Diseases, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: The combination of electronic health records (EHRs) with genetic data has ushered in the next wave of complex disease genetics. Population-based biobanks and other large cohorts provide sufficient sample sizes to identify novel genetic associations across the hundreds to thousands of phenotypes gleaned from EHRs. In this review, we summarize the current state of these EHR-linked biobanks, explore ongoing methods development in the field and highlight recent discoveries of genetic associations. We enumerate the many existing biobanks with EHRs linked to genetic data, many of which are available to researchers via application and contain sample sizes >50 000. We also discuss the computational and statistical considerations for analysis of such large datasets including mixed models, phenotype curation and cloud computing. Finally, we demonstrate how genome-wide association studies and phenome-wide association studies have identified novel genetic findings for complex diseases, specifically cardiometabolic traits. As more researchers employ innovative hypotheses and analysis approaches to study EHR-linked biobanks, we anticipate a richer understanding of the genetic etiology of complex diseases.
Published: 2018
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29. Within-family studies for Mendelian randomization: avoiding dynastic, assortative mating, and population stratification biases

Author: Gunnhild Åberge Vie, Gibran Hemani, Yoonsu Cho, Sean Harrison, John L. Hopper, Alexandra Havdahl, Shuai Li, Michael C. Neale, Ben Michael Brumpton, Nancy L. Pedersen, Wei-Min Chen, Neil M Davies, Laurence J. Howe, Kristian Hveem, George Davey Smith, Michel G. Nivard, Cristen J. Willer, Amanda Hughes, Dorret I. Boomsma, Johan Håkon Bjørngaard, Fernando Pires Hartwig, Chandra A. Reynolds, Laura D Howe, Elliot M. Tucker-Drob, Andrew D. Grotzinger, Bjørn Olav Åsvold, David M. Evans, Eleanor Sanderson, Jaakko Kaprio, and Tim T Morris
Subjects: 0303 health sciences, education.field_of_study, Offspring, Population, Assortative mating, Biology, Population stratification, Educational attainment, 03 medical and health sciences, Family studies, 0302 clinical medicine, Causal inference, Mendelian randomization, education, 030217 neurology & neurosurgery, 030304 developmental biology, Demography
Abstract: Mendelian randomization (MR) is a widely-used method for causal inference using genetic data. Mendelian randomization studies of unrelated individuals may be susceptible to bias from family structure, for example, through dynastic effects which occur when parental genotypes directly affect offspring phenotypes. Here we describe methods for within-family Mendelian randomization and through simulations show that family-based methods can overcome bias due to dynastic effects. We illustrate these issues empirically using data from 61,008 siblings from the UK Biobank and Nord-Trøndelag Health Study. Both within-family and population-based Mendelian randomization analyses reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while MR estimates from population-based samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects largely disappeared in within-family MR analyses. We found differences between population-based and within-family based estimates, indicating the importance of controlling for family effects and population structure in Mendelian randomization studies.
Published: 2019
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30. SNPs associated withHHIPexpression have differential effects on lung function in males and females

Author: Peter D. Sly, Re Foong, Ozren Polasek, Nicole Probst-Hensch, Ian P. Hall, Graham L. Hall, Tobin, Pirro G. Hysi, Teemu Palviainen, Mika Kähönen, Veronique Vitart, Louise V. Wain, Carl A. Melbourne, Don D. Sin, Anna L. Guyatt, Henry Völzke, Ca Wang, Katherine A. Fawcett, David J. Porteous, John M. Starr, Claudia Langenberg, Igor Rudan, Ke Hao, Stefan Weiss, Terho Lehtimäki, Kirsi H. Pietiläinen, David M. Evans, Ian J. Deary, Jian'an Luan, James F. Wilson, David P. Strachan, Taina Rantanen, Catherine John, Nicola Pirastu, O T Raitakari, Berge M van den, Karina Patasova, Claudia Flexeder, Medea Imboden, Thibaud Boutin, Mangino Massimo, Archie Campbell, Lucija Klaric, Leo-Pekka Lyytikäinen, Nick Shrine, Sebastian May-Wilson, Beate Stubbe, Ralf Ewert, Dirk Keidel, Sarah E. Harris, Tim D. Spector, Ma'en Obeidat, John Henderson, Cosetta Minelli, Moksnes, Raquel Granell, Blair H. Smith, Arnulf Langhammer, Craig E. Pennell, Nicholas J. Wareham, Caroline Hayward, Ben Michael Brumpton, Yohan Bossé, Peter K. Joshi, Susan M. Ring, Sandosh Padmanabhan, Cristen J. Willer, Kristian Hveem, Deborah Jarvis, J Kaprio, Laura Portas, and Anne Richmond
Subjects: Spirometry, 0303 health sciences, COPD, medicine.medical_specialty, Lung, medicine.diagnostic_test, Single-nucleotide polymorphism, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Endocrinology, 030228 respiratory system, Internal medicine, medicine, SNP, Allele, Beta (finance), Lung function, 030304 developmental biology
Abstract: Adult lung function is highly heritable and 279 genetic loci were recently reported as associated with spirometry-based measures of lung function. Though lung development and function differ between males and females throughout life, there has been no genome-wide study to identify genetic variants with differential effects on lung function in males and females. Here, we present the first genome-wide genotype-by-sex interaction study on four lung function traits in 303,612 participants from the UK Biobank. We detected five SNPs showing genome-wide significant (P−8) interactions with sex on lung function, as well as 21 suggestively significant interactions (P−6). The strongest sex interaction signal came from rs7697189 at 4:145436894 on forced expiratory volume in 1 second (FEV1) (P = 3.15 × 10−15), and was replicated (P = 0.016) in 75,696 individuals in the SpiroMeta consortium. Sex-stratified analyses demonstrated that the minor (C) allele of rs7697189 increased lung function to a greater extent in males than females (untransformed FEV1β = 0.028 [SE 0.0022] litres in males vs β = 0.009 [SE 0.0014] litres in females), and this effect was not accounted for by differential effects on height, smoking or age at puberty. This SNP resides upstream of the gene encoding hedgehog-interacting protein (HHIP) and has previously been reported for association with lung function andHHIPexpression in lung tissue. In our analyses, whileHHIPexpression in lung tissue was significantly different between the sexes with females having higher expression (most significant probeset P=6.90 × 10−6) after adjusting for age and smoking, rs7697189 did not demonstrate sex differential effects on expression. Establishing the mechanism by whichHHIPSNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases, such as chronic obstructive pulmonary disease (COPD), in both sexes.
Published: 2019
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31. Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank

Author: Ida Surakka, Alexander Lopez, Lukas Habegger, Shareef Khalid, William J Salerno, Andrew Blumenfeld, Bin Ye, Jeffrey G. Reid, Ashutosh K. Pandey, Alicia Hawes, John D. Overton, Giovanni Coppola, Jonathan Marchini, Wendy K. Chung, David J. Carey, David H. Ledbetter, Kristian Hveem, Aris N. Economides, Cristopher V. Van Hout, Kavita Praveen, Cristen J. Willer, Joshua D. Backman, Anthony Marcketta, Ioanna Tachmazidou, Marcus B. Jones, O’Dushlaine Colm, John Penn, Joseph B. Leader, Leland Barnard, Daren Liu, George D. Yancopoulos, Michael N. Cantor, Suganthi Balasubramanian, Laura M. Yerges-Armstrong, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, John C. Whittaker, Nilanjana Banerjee, Aris Baras, Gonçalo R. Abecasis, Claudia Schurmann, Robert A. Scott, Evan Maxwell, Matthew R. Nelson, Jeffrey Staples, Ashish Yadav, Joshua D. Hoffman, Lon R. Cardon, and Alexander H. Li
Subjects: education.field_of_study, Genotype, Population, Disease, Computational biology, Biology, education, Exome, Gene, Biobank, Exome sequencing, Loss function
Abstract: SUMMARYThe UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the first tranche of large-scale exome sequence data for 49,960 study participants, revealing approximately 4 million coding variants (of which ~98.4% have frequency < 1%). The data includes 231,631 predicted loss of function variants, a >10-fold increase compared to imputed sequence for the same participants. Nearly all genes (>97%) had ≥1 predicted loss of function carrier, and most genes (>69%) had ≥10 loss of function carriers. We illustrate the power of characterizing loss of function variation in this large population through association analyses across 1,741 phenotypes. In addition to replicating a range of established associations, we discover novel loss of function variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical significance in this population, finding that 2% of the population has a medically actionable variant. Additionally, we leverage the phenotypic data to characterize the relationship between rare BRCA1 and BRCA2 pathogenic variants and cancer risk. Exomes from the first 49,960 participants are now made accessible to the scientific community and highlight the promise offered by genomic sequencing in large-scale population-based studies.
Published: 2019
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32. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Author: Russell P. Tracy, Mollie A. Minear, James B. Meigs, Amol C. Shetty, David Van Den Berg, Yii-Der Ida Chen, Nona Sotoodehnia, Kent D. Taylor, Soren Germer, Adolfo Correa, John Barnard, Emelia J. Benjamin, Weihong Tang, Zachary A. Szpiech, Sebastian Schoenherr, Kristin G. Ardlie, Anna Köttgen, Tanika N. Kelly, Leslie A. Lange, Michelle Daya, Dan M. Roden, Lori Garman, Xutong Zhao, Lawrence F. Bielak, Edwin K. Silverman, Daniel E. Weeks, Gina M. Peloso, Jill M. Johnsen, Hyun Min Kang, Lukas Forer, Jerome I. Rotter, Stephen T. McGarvey, Wendy S. Post, Weiniu Gan, Stephanie M. Fullerton, Jedidiah Carlson, Brian Custer, Nora Franceschini, Alvaro Alonso, Brian L. Browning, Michael H. Cho, André Corvelo, Stacey Gabriel, Xiuqing Guo, Angel C.Y. Mak, Michael Boehnke, Yingze Zhang, Timothy A. Thornton, Douglas P. Kiel, Ingo Ruczinski, Sudha Seshadri, Seung-been Lee, Scott I. Vrieze, Charles Kooperberg, Stephanie M. Gogarten, John Blangero, Brandon Chalazan, Seung Hoan Choi, Dawood Darbar, Braxton D. Mitchell, Alisa K. Manning, Anne-Katrin Emde, Xihong Lin, D. C. Rao, Eimear E. Kenny, Christine M. Albert, Xiaowen Tian, Allison E. Ashley-Koch, Mina K. Chung, Pradeep Natarajan, Rebecca L. Beer, Stella Aslibekyan, Jiang He, Patrick T. Ellinor, James F. Casella, Richard A. Gibbs, Alanna C. Morrison, Clary B. Clish, Nancy L. Heard-Costa, Susan R. Heckbert, Daniel N. Harris, Myriam Fornage, M. Benjamin Shoemaker, Kari E. North, Courtney G. Montgomery, Sanghamitra Mohanty, Lewis C. Becker, George J. Papanicolaou, Chunyu Liu, Michael D. Kessler, Susan K. Dutcher, Marguerite R. Irvin, Daniel Levy, Karine A. Viaud-Martinez, Joanne E. Curran, Jonathon LeFaive, Dawn L. DeMeo, Mark T. Gladwin, Quenna Wong, Andrea Natale, Adrienne M. Stilp, Patricia A. Peyser, Robert Klemmer, Jessica Lasky-Su, Donald W. Bowden, Kathryn L. Lunetta, Rasika A. Mathias, Brian E. Cade, Kathleen C. Barnes, Daniel Taliun, Douglas Loesch, Sharon R. Browning, Joanne M. Murabito, Esteban G. Burchard, Sarah A Gagliano Taliun, Daniel J. Gottlieb, Timothy D. O’Connor, Deborah A. Meyers, Jennifer A. Brody, Ryan D. Hernandez, Andrew D. Johnson, Eric Boerwinkle, Sebastian Zöllner, Ruth J. F. Loos, Nicholas L. Smith, Gonçalo R. Abecasis, Jennifer A. Smith, Michael E. Hall, Lu-Chen Weng, Jeffrey R. O'Connell, Kenneth Rice, Donna K. Arnett, Nicholette D. Palmer, Bruce S. Weir, L. Adrienne Cupples, Barbara A. Konkle, Paul L. Auer, Cathy C. Laurie, Julie L. Mikulla, Deborah A. Nickerson, Alexander P. Reiner, Chloé Sarnowski, Raul Torres, Susan Redline, Mariza de Andrade, Vivien A. Sheehan, Cashell E. Jaquish, Pankaj Qasba, R. Graham Barr, Scott T. Weiss, Ani Manichaikul, Robert E. Gerszten, Albert V. Smith, Steven A. Lubitz, Cristen J. Willer, Michael C. Zody, Jeong-Sun Seo, Diane Fatkin, Christian Fuchsberger, François Aguet, Sharon L.R. Kardia, James G. Wilson, Marilyn J. Telen, Ramachandran S. Vasan, Nathan Pankratz, Keng-Han Lin, Shannon Kelly, Wayne E. Clarke, Sarah C. Nelson, May E. Montasser, Stephen S. Rich, Sayantan Das, Thomas W. Blackwell, Bruce M. Psaty, Leslie S. Emery, Achilleas N. Pitsillides, and David D. McManus
Subjects: Whole genome sequencing, 0303 health sciences, Genotype imputation, Disease, Computational biology, Biology, Precision medicine, Phenotype, Genome, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030217 neurology & neurosurgery, 030304 developmental biology, Reference genome
Abstract: Summary paragraphThe Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency
Published: 2019
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33. Genome-scale CRISPR screening for modifiers of cellular LDL uptake

Author: Paul J. Lascuna, Emily J. Sherman, David Ginsburg, Brian T. Emmer, Cristen J. Willer, and Sarah E. Graham
Subjects: Genetic Screens, Cancer Research, Gene Identification and Analysis, Gene Expression, Genome-wide association study, QH426-470, 030204 cardiovascular system & hematology, Biochemistry, Synthetic Genome Editing, Genome Engineering, Guide RNA, chemistry.chemical_compound, 0302 clinical medicine, CRISPR, Genetics (clinical), Regulation of gene expression, 0303 health sciences, Crispr, Hep G2 Cells, Genomics, Lipids, Endocytosis, Cell biology, Lipoproteins, LDL, Nucleic acids, Cholesterol, Engineering and Technology, Synthetic Biology, lipids (amino acids, peptides, and proteins), RNA, Guide, Kinetoplastida, Research Article, Hypercholesterolemia, Bioengineering, Library Screening, Biology, Research and Analysis Methods, 03 medical and health sciences, Gene Types, Genome-Wide Association Studies, Genetics, Humans, Gene Regulation, Molecular Biology Techniques, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Molecular Biology Assays and Analysis Techniques, Biology and life sciences, Genome, Human, Computational Biology, Human Genetics, Synthetic Genomics, Atherosclerosis, Genome Analysis, Gene Expression Regulation, Receptors, LDL, chemistry, LDL receptor, Hepatocytes, RNA, Regulator Genes, CRISPR-Cas Systems, Genetic screen
Abstract: Hypercholesterolemia is a causal and modifiable risk factor for atherosclerotic cardiovascular disease. A critical pathway regulating cholesterol homeostasis involves the receptor-mediated endocytosis of low-density lipoproteins into hepatocytes, mediated by the LDL receptor. We applied genome-scale CRISPR screening to query the genetic determinants of cellular LDL uptake in HuH7 cells cultured under either lipoprotein-rich or lipoprotein-starved conditions. Candidate LDL uptake regulators were validated through the synthesis and secondary screening of a customized library of gRNA at greater depth of coverage. This secondary screen yielded significantly improved performance relative to the primary genome-wide screen, with better discrimination of internal positive controls, no identification of negative controls, and improved concordance between screen hits at both the gene and gRNA level. We then applied our customized gRNA library to orthogonal screens that tested for the specificity of each candidate regulator for LDL versus transferrin endocytosis, the presence or absence of genetic epistasis with LDLR deletion, the impact of each perturbation on LDLR expression and trafficking, and the generalizability of LDL uptake modifiers across multiple cell types. These findings identified several previously unrecognized genes with putative roles in LDL uptake and suggest mechanisms for their functional interaction with LDLR., Author summary The level of cholesterol circulating in the blood in low-density lipoproteins (LDL) is an important determinant of overall risk for cardiovascular diseases, including heart attack and stroke. This level is regulated by the removal of LDL from circulation into liver cells. While many molecules involved in LDL uptake have been characterized, we hypothesized that other currently unrecognized genetic interactions are also involved in this process. We therefore applied CRISPR-mediated genome editing to systematically test the contribution of every gene in the human genome to the uptake of LDL by a liver-derived cell line. We synthesized a secondary CRISPR library targeting the top candidate genes from this initial genome-wide screen to confirm their role in LDL uptake and to test their influence on other cellular functions. Our findings confirm the role of genes previously known to participate in LDL uptake and also provide novel insight into the overall regulation of this process.
Published: 2021
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34. Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

Author: Anne-Claire Vergnaud, Nauder Faraday, Tim Kacprowski, Lisa R. Yanek, Oscar H. Franco, Yongmei Liu, Andreas Greinacher, Gina M. Peloso, Cristen J. Willer, Leslie A. Lange, Eric S. Torstenson, Reedik Mägi, Jeanette Erdmann, Ethan M. Lange, Deborah A. Nickerson, Henry Völzke, David R. Crosslin, Gunnar Engström, Albert V. Smith, André G. Uitterlinden, Salman M. Tajuddin, W. David Hill, Diane M. Becker, Paul Elliot, Caterina Vacchi-Suzzi, Linda M. Polfus, Traci M. Bartz, Nathalie Chami, Abbas Dehghan, Mike A. Nalls, John D. Eicher, Leo-Pekka Lyytikäinen, Evelin Mihailov, Uwe Völker, Caroline Hayward, Ioanna Tzoulaki, Myriam Fornage, Marju Orho-Melander, Mary Cushman, Lars Wallentin, Terho Lehtimäki, Ayush Giri, Laura M. Raffield, Lewis C. Becker, Yingchang Lu, Emma Raitoharju, Sekar Kathiresan, Simon de Denus, Ruth J. F. Loos, James S. Floyd, Dawn M. Waterworth, James G. Wilson, Nathan Pankratz, Lenore J. Launer, Andrew D. Johnson, Andrew J. Slater, Jean-Claude Tardif, Raha Pazoki, Evangelos Evangelou, Kenneth Rice, Harvey D. White, Marie-Pierre Dubé, Frank J. A. van Rooij, Akihiro Nomura, Tamara B. Harris, Vilmundur Gudnason, Gonçalo R. Abecasis, Alan B. Zonderman, Guillaume Lettre, Todd L. Edwards, Amber A. Burt, Ani Manichaikul, Heribert Schunkert, Ming-Huei Chen, Ian J. Deary, Michelle L. O'Donoghue, Jennifer A. Brody, Russell P. Tracy, Tõnu Esko, Mika Kähönen, Panos Deloukas, Eric Boerwinkle, Rasika A. Mathias, Dajiang J. Liu, Jin Li, Santhi K. Ganesh, David C. Liewald, Paul L. Auer, Digna R. Velez Edwards, Erwin P. Bottinger, Nina Mononen, Claudia Schurmann, Michele K. Evans, John M. Starr, Thomas Thiele, Jussi Hernesniemi, Jerome I. Rotter, Rakale C. Quarells, He Gao, Kjell Nikus, Stephen S. Rich, Heather M. Highland, Bruce M. Psaty, Ursula M. Schick, Andres Metspalu, Melissa A. Richard, Neil A. Zakai, Olle Melander, John D. Rioux, Olli T. Raitakari, Alexander P. Reiner, Joel N. Hirschhorn, Nilesh J. Samani, Epidemiology, Internal Medicine, Home Office, National Institute for Health Research, and Medical Research Council (MRC)
Subjects: 0301 basic medicine, Blood Platelets, Male, CARDIoGRAM Exome Consortium, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Myocardial Infarction Genetics Consortium, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Platelet, Exome, Genetics(clinical), Mean platelet volume, Allele frequency, Genotyping, Genetics (clinical), Genetics & Heredity, Platelet Count, ta1184, Genetic Variation, Global Lipids Genetics Consortium, 11 Medical And Health Sciences, 06 Biological Sciences, FCER1A, Genetic architecture, 030104 developmental biology, Hemostasis, Immunology, Female, Mean Platelet Volume, Genome-Wide Association Study
Abstract: Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
Published: 2016
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35. Biological and clinical insights from genetics of insomnia symptoms

Author: Rebecca C Richmond, Heming Wang, David W. Ray, Jacqueline M. Lane, Annemarie I. Luik, David A. Bechtold, Max A. Little, Yanwei Song, Simon D. Kyle, Michael N. Weedon, Mary E. Haas, Krishna G. Aragam, Debbie A Lawlor, Martin K. Rutter, Cristen J. Willer, Jessica Tyrrell, Susan Redline, Samuel E. Jones, Vincent T. van Hees, John-Anker Zwart, Kai Spiegelhalder, Barbara Schormair, Krunal Patel, Timothy M. Frayling, Andrew S. I. Loudon, Brian E. Cade, Robin N Beaumont, Bendik S. Winsvold, Sekar Kathiresan, Andrew R. Wood, Juliane Winkelmann, Richa Saxena, Ben Michael Brumpton, Hunt All In Sleep, Linn B Strand, Kristian Hveem, John W. Winkelman, Shaun Purcell, Frank A.J.L. Scheer, Jonas B. Nielsen, Hassan S. Dashti, Chen Zhao, Simon G. Anderson, Jack Bowden, and Epidemiology
Subjects: Adult, Male, medicine.medical_specialty, Gene Expression, Disease, Biology, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Sleep Initiation and Maintenance Disorders, mental disorders, Genetics, medicine, Insomnia, Humans, Genetic Predisposition to Disease, Restless legs syndrome, 030304 developmental biology, Aged, 0303 health sciences, Ubiquitin, Case-control study, Middle Aged, medicine.disease, Biobank, Pathophysiology, 3. Good health, Case-Control Studies, Proteolysis, Female, Self Report, medicine.symptom, Sleep, 030217 neurology & neurosurgery
Abstract: Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n = 14,923 cases, 47,610 controls), physician-diagnosed insomnia in Partners Biobank (n = 2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms and subjective well-being., Editorial summary: Genome-wide association analyses identify 57 loci associated with insomnia symptoms and evidence of shared genetic architecture between insomnia and cardio-metabolic, behavioral, psychiatric and reproductive traits.
Published: 2018
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36. Genome-wide association analysis of excessive daytime sleepiness identifies 42 loci that suggest phenotypic subgroups

Author: Max A. Little, Michael N. Weedon, Jack Bowden, Rebecca C Richmond, Shaun Purcell, Hanna Ollila, Frank A.J.L. Scheer, Jacqueline M. Lane, Kristian Hveem, Sonja Sulkava, Cristen J. Willer, Samuel E. Jones, Kai Spiegelhalder, Heming Wang, Linn B Strand, Andrew R. Wood, Krunal Patel, Timothy M. Frayling, Andrew S. I. Loudon, Richa Saxena, Debbie A Lawlor, Martin K. Rutter, Jessica Tyrrell, Ben Michael Brumpton, David A. Bechtold, John-Anker Zwart, Jonas B. Nielsen, Katri Kantojärvi, Hassan S. Dashti, Vincent T. van Hees, Brian E. Cade, Tamar Sofer, Richard Emsley, Simon G. Anderson, Yanwei Song, Simon D. Kyle, Kati Kristiansson, Xiaofeng Zhu, Susan Redline, Tiina Paunio, Bendik S. Winsvold, and David W. Ray
Subjects: Genetics, 0303 health sciences, education.field_of_study, Population, Chronotype, Excessive daytime sleepiness, Mendelian Randomization Analysis, Single-nucleotide polymorphism, Genome-wide association study, Biology, medicine.disease, Obesity, 03 medical and health sciences, 0302 clinical medicine, Insomnia, medicine, medicine.symptom, education, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. We identified 42 loci for self-reported EDS in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirmed the aggregate effect of a genetic risk score of 42 SNPs on EDS in independent Scandinavian cohorts and on other sleep disorders (restless leg syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). Strong genetic correlations were also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing. EDS variants clustered into two predominant composite phenotypes - sleep propensity and sleep fragmentation - with the former showing stronger evidence for enriched expression in central nervous system tissues, suggesting two unique mechanistic pathways. Mendelian randomization analysis indicated that higher BMI is causally associated with EDS risk, but EDS does not appear to causally influence BMI.
Published: 2018
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37. Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

Author: Jonas B. Nielsen, Matthew Zawistowski, Matthew G. Sampson, Gonçalo R. Abecasis, Cristen J. Willer, Ida Surakka, Anne Heidi Skogholt, Hyun Min Kang, Sarah E. Graham, Wei Zhou, Maiken Elvestad Gabrielsen, Stein Hallan, Damian Fermin, Lars G. Fritsche, Chad M. Brummett, Sachin Kheterpal, Kristian Hveem, Seunggeun Lee, and Solfrid Romundstad
Subjects: 0303 health sciences, Kidney, SLC47A1, biology, Renal function, Kidney development, Genome-wide association study, medicine.disease, Bioinformatics, Phenotype, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Meta-analysis, medicine, biology.protein, 030212 general & internal medicine, 030304 developmental biology, Kidney disease
Abstract: Chronic Kidney Disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. Previous genome-wide association study (GWAS) meta-analyses of CKD and eGFR or related phenotypes have identified a number of variants associated with kidney function, but these only explain a fraction of the variability in kidney phenotypes attributed to genetic components. To extend these studies, we analyzed data from the Nord-Trøndelag Health Study (HUNT), which is more densely imputed than previous studies, and performed a GWAS meta-analysis of eGFR with publicly available summary statistics, more than doubling the sample size of previous meta-analyses. We identified 147 loci (53 novel loci) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Moreover, genes at these loci show enriched expression in urogenital tissues and highlight gene sets known to play a role in kidney function. In addition, sex-stratified analysis identified three regions (prioritized genes:PPM1J, MCL1, andSLC47A1) with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD but improve detection only modestly compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.
Published: 2018
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38. A genome scan for genes underlying adult body size differences between Central African hunter-gatherers and farmers

Author: Paul Verdu, Alain Froment, Trevor J. Pemberton, Noah A. Rosenberg, Evelyne Heyer, Noémie S. Becker, Sylvie Le Bomin, Cristen J. Willer, Barry S. Hewlett, Eco-Anthropologie et Ethnobiologie (EAE), and Muséum national d'Histoire naturelle (MNHN)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Rural Population, 0301 basic medicine, Linkage disequilibrium, Genotype, Genetic genealogy, [SDV]Life Sciences [q-bio], Black People, Single-nucleotide polymorphism, Biology, Sitting, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Africa, Central, Gene, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Genome, Human, Phenotype, Body Height, 030104 developmental biology, Female, Body mass index, 030217 neurology & neurosurgery, Demography
Abstract: The evolutionary and biological bases of the Central African "pygmy" phenotype, a characteristic of rainforest hunter-gatherers defined by reduced body size compared with neighboring farmers, remain largely unknown. Here, we perform a joint investigation in Central African hunter-gatherers and farmers of adult standing height, sitting height, leg length, and body mass index (BMI), considering 358 hunter-gatherers and 169 farmers with genotypes for 153,798 SNPs. In addition to reduced standing heights, hunter-gatherers have shorter sitting heights and leg lengths and higher sitting/standing height ratios than farmers and lower BMI for males. Standing height, sitting height, and leg length are strongly correlated with inferred levels of farmer genetic ancestry, whereas BMI is only weakly correlated, perhaps reflecting greater contributions of non-genetic factors to body weight than to height. Single- and multi-marker association tests identify one region and eight genes associated with hunter-gatherer/farmer status, and 24 genes associated with the height-related traits. Many of these genes have putative functions consistent with roles in determining their associated traits and the pygmy phenotype, and they include three associated with standing height in non-Africans (PRKG1, DSCAM, MAGI2). We find evidence that European height-associated SNPs or variants in linkage disequilibrium with them contribute to standing- and sitting-height determination in Central Africans, but not to the differential status of hunter-gatherers and farmers. These findings provide new insights into the biological basis of the pygmy phenotype, and they highlight the potential of cross-population studies for exploring the genetic basis of phenotypes that vary naturally across populations.
Published: 2018
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39. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Author: Ching-Ti Liu, Michael Boehnke, George Dedoussis, Sophie V. Eastwood, Ruth J. F. Loos, Keng-Hung Lin, Denis Rybin, Fredrik Karpe, Martina Müller-Nurasyid, Michael A. Province, Alison D. Murray, Bo Isomaa, Eirini Marouli, Konstantin Strauch, Michael Preuss, Paul M. Ridker, Jette Bork-Jensen, Albert V. Smith, Hugoline G. de Haan, Wayne Huey-Herng Sheu, Barbara Thorand, Wolfgang Rathmann, Lawrence F. Bielak, Peter Kovacs, Marit E. Jørgensen, Jennifer Wessel, Danish Saleheen, Jung-Jin Lee, James B. Meigs, Veikko Salomaa, Alena Stančáková, Tibor V. Varga, Hidetoshi Kitajima, Inês Barroso, Kent D. Taylor, Claudia Langenberg, Yoon Shin Cho, Joanna M. M. Howson, Andrew T. Hattersley, Marie-France Hivert, Markku Laakso, Kai-Uwe Eckardt, Bram P. Prins, Matthias B. Schulze, Andrew D. Morris, Susanne Jäger, Francis S. Collins, Kristi Läll, Xu Lin, Anette Varbo, Benjamin Lehne, Girish N. Nadkarni, Jonathan Marchini, Daniel I. Chasman, Michael Stumvoll, Mark O. Goodarzi, Cécile Lecoeur, Philippe M. Frossard, Noël P. Burtt, Frank Kee, Jasmina Kravic, Alain G. Bertoni, Ivan Brandslund, Najaf Amin, Lenore J. Launer, Oluf Pedersen, Johanna Kuusisto, Line Rode, Eleftheria Zeggini, Yingchang Lu, Markus Perola, Helen R. Warren, André G. Uitterlinden, Hanieh Yaghootkar, Torben Hansen, Harald Grallert, Annemari Käräjämäki, Abbas Dehghan, Gina M. Peloso, Yii-Der Ida Chen, Man Li, Shaofeng Huo, Lars Lind, Karen L. Mohlke, Adrienne Tin, Yang Hai, Renée de Mutsert, Gudmar Thorleifsson, Marie Moitry, Sune F. Nielsen, Sara M. Willems, Matthias Wuttke, Weihua Zhang, Young-Jin Kim, Giovanni Malerba, Richard A. Jensen, Loic Yengo, Mickaël Canouil, Kurt Lohman, Robert A. Scott, Tamara B. Harris, Ruifang Li-Gao, Florian Kronenberg, Anke Tönjes, Bok-Ghee Han, Krista Fischer, Thomas Meitinger, James S. Pankow, Jaakko Tuomilehto, Adam S. Butterworth, Jerome I. Rotter, Olov Rolandsson, Xiuqing Guo, Cramer Christensen, Marie Loh, Elizabeth Selvin, Bong-Jo Kim, Audrey Y. Chu, Reedik Mägi, Josée Dupuis, Anna Köttgen, Jean Ferrières, Jin Li, Robert Sladek, Leslie A. Lange, Niels Grarup, Roberta McKean-Cowdin, Cristen J. Willer, Jose C. Florez, Valgerdur Steinthorsdottir, Karina Meidtner, Annette Peters, Børge G. Nordestgaard, Rajiv Chowdhury, Ioanna Ntalla, Emma Ahlqvist, Leif Groop, Nicholas J. Wareham, Kerrin S. Small, Tiinamaija Tuomi, Cecilia M. Lindgren, Katharine R. Owen, Giovanni Gambaro, Cornelia M. van Duijn, Dennis O. Mook-Kanamori, Kenneth Rice, Erik Ingelsson, Colin N. A. Palmer, Sharon L.R. Kardia, Neil R. Robertson, Dajiang J. Liu, Sebastian Schönherr, Daniel Taliun, Sekar Kathiresan, James G. Wilson, Ping An, Patricia A. Peyser, Matthias Blüher, Frits R. Rosendaal, John C. Chambers, Caroline Hayward, Shoaib Afzal, Fernando Rivadineira, Marielisa Graff, Pranav Yajnik, Vasiliki Mamakou, Juan Fernandez Tajes, Stefan Gustafsson, Heather M. Highland, Vilmantas Giedraitis, Andrew R. Wood, Saima Afaq, Jaspal S. Kooner, Megan L. Grove, Jennifer A. Brody, Andrew P. Morris, James P. Cook, Praveen Surendran, Jennifer Kriebel, Heikki A. Koistinen, Kari Stefansson, Anders Rosengren, Rainer Rauramaa, Satu Männistö, Oscar H. Franco, Yongmei Liu, N. William Rayner, Blair H. Smith, Erwin P. Bottinger, Ayse Demirkan, Allan Linneberg, Jonathan Marten, Huaixing Li, Sung Soo Kim, Sophie Hackinger, Cristina Bombieri, Lia B. Bang, Jun Liu, Asif Rasheed, Tim D. Spector, Paul W. Franks, Mark I. McCarthy, Heiner Boeing, Anne E. Justice, Vilmundur Gudnason, Sohee Han, Unnur Thorsteinsdottir, Panos Deloukas, Naveed Sattar, Eric Boerwinkle, Martin Ingelsson, John Danesh, Vassily Trubetskoy, Marco M Ferrario, Marju Orho-Melander, Wei Gan, Philippe Froguel, Symen Ligthart, Susan R. Heckbert, Jie Yao, Anne Tybjærg-Hansen, Robin Young, Daniel R. Witte, Anubha Mahajan, Peter Almgren, Timothy M. Frayling, Tanya M. Teslovich, Matt Neville, Philippe Amouyel, Wei Zhao, Andres Metspalu, Yao Hu, Olle Melander, Kari Kuulasmaa, Jason Flannick, Torben Jørgensen, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Rohit Varma, Epidemiology, and Internal Medicine
Subjects: 0301 basic medicine, Male, Inference, Genome-wide association study, Whole Exome Sequencing, 0302 clinical medicine, type 2 diabetes, coding variant associations signals, mechanistic inference, fine mapping, Coding region, Chromosome Mapping/statistics & numerical data, European Continental Ancestry Group/genetics, CONFERS SUSCEPTIBILITY, Exome sequencing, 11 Medical and Health Sciences, Genetics, Genetics & Heredity, 0303 health sciences, MAGIC Consortium, Chromosome Mapping, Whole Exome Sequencing/statistics & numerical data, Identification (information), RARE VARIANTS, LOW-FREQUENCY, Female, ExomeBP Consortium, Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, Posterior probability, European Continental Ancestry Group, 030209 endocrinology & metabolism, Context (language use), Computational biology, Biology, GENOTYPE IMPUTATION, Article, White People, GENETIC ARCHITECTURE, 03 medical and health sciences, SDG 3 - Good Health and Well-being, QUALITY-CONTROL, Exome Sequencing, Genome-Wide Association Study/statistics & numerical data, Journal Article, GIANT Consortium, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Alleles, Genetic association, 030304 developmental biology, FATTY LIVER-DISEASE, Science & Technology, Genetic Variation, 06 Biological Sciences, Genetic architecture, Minor allele frequency, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 2/classification, 030217 neurology & neurosurgery, Coding (social sciences), Genome-Wide Association Study, Developmental Biology
Abstract: Identification of coding variant associations for complex diseases offers a direct route to biological insight, but is dependent on appropriate inference concerning the causal impact of those variants on disease risk. We aggregated coding variant data for 81,412 type 2 diabetes (T2D) cases and 370,832 controls of diverse ancestry, identifying 40 distinct coding variant association signals (at 38 loci) reaching significance (p−7). Of these, 16 represent novel associations mapping outside known genome-wide association study (GWAS) signals. We make two important observations. First, despite a threefold increase in sample size over previous efforts, only five of the 40 signals are driven by variants with minor allele frequency 1.29. Second, we used GWAS data from 50,160 T2D cases and 465,272 controls of European ancestry to fine-map these associated coding variants in their regional context, with and without additional weighting to account for the global enrichment of complex trait association signals in coding exons. At the 37 signals for which we attempted fine-mapping, we demonstrate convincing support (posterior probability >80% under the “annotation-weighted” model) that coding variants are causal for the association at 16 (including novel signals involving POC5 p.His36Arg, ANKH p.Arg187Gln, WSCD2 p.Thr113Ile, PLCB3 p.Ser778Leu, and PNPLA3 p.Ile148Met). However, at 13 of the 37 loci, the associated coding variants represent “false leads” and naïve analysis could have led to an erroneous inference regarding the effector transcript mediating the signal. Accurate identification of validated targets is dependent on correct specification of the contribution of coding and non-coding mediated mechanisms at associated loci.
Published: 2018
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40. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center
Subjects: 0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Published: 2018
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41. Recent developments in genome and exome-wide analyses of plasma lipids

Author: Stephen S. Rich, Leslie A. Lange, and Cristen J. Willer
Subjects: Cancer genome sequencing, Endocrinology, Diabetes and Metabolism, Population, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Genome, Genetics, Animals, Humans, Exome, Genetic Predisposition to Disease, Molecular Targeted Therapy, education, Molecular Biology, Exome sequencing, Dyslipidemias, Hypolipidemic Agents, education.field_of_study, Nutrition and Dietetics, Sequence Analysis, DNA, Cell Biology, Lipid Metabolism, Lipids, Genetic architecture, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, Genome-Wide Association Study, Personal genomics
Abstract: Purpose of review Genome-wide association scans (GWAS) have identified over 100 human loci associated with variation in lipids. The identification of novel genes and variants that affect lipid levels is made possible by next-generation sequencing, rare variant discovery and analytic advances. The current status of the genetic basis of lipid traits will be presented. Recent findings Expansion of GWAS sample sizes for lipid traits has not substantially increased the proportion of trait variance explained by common genetic variants (less than 15% of trait variation captured). Although GWAS has discovered novel loci and pathways with putative biological function and impact on cardiovascular disease risk, discovery of the genes in these loci remains challenging. Exome sequencing promises to identify genes with protein-coding variants with a large impact on lipids, as shown for LDL-cholesterol levels associated with novel (PNPLA5) and known (LDLR, PCSK9, APOB) genes. Summary Current results have increased our understanding of the genetic architecture of lipids, expanding the range of effect and frequency for variants identified for lipid traits. Identification of novel lipid-associated gene variants, even if small in effect or rare in the population, could provide important novel drug targets and biological pathways for dyslipidemia.
Published: 2015
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42. A Genome Scan for Genes Underlying Adult Body Size Differences between Central African Pygmies and their Non-Pygmy Neighbors

Author: Cristen J. Willer, Noémie S. Becker, Noah A. Rosenberg, Trevor J. Pemberton, Evelyne Heyer, Sylvie Le Bomin, Alain Froment, Barry S. Hewlett, and Paul Verdu
Subjects: 2. Zero hunger, Genetics, 0303 health sciences, 030305 genetics & heredity, Genetic admixture, Single-nucleotide polymorphism, 15. Life on land, Biology, Sitting, Phenotype, Genetic architecture, 03 medical and health sciences, Evolutionary biology, Trait, Adaptation, Body mass index, 030304 developmental biology
Abstract: BackgroundCentral African hunter-gatherer Pygmy populations have reduced body size compared with their often much larger agricultural non-Pygmy neighbors, potentially reflecting adaptation to the anatomical and physiological constraints of their lifestyle in tropical rainforests. Earlier studies investigating the genetics of the pygmy phenotype have focused on standing height, one aspect of this complex phenotype that is itself a composite of skeletal components with different growth patterns. Here, we extend the investigations of standing height to the variability and genetic architecture of sitting height and subischial leg length as well as body mass index (BMI) in a sample of 406 unrelated West Central African Pygmies and non-Pygmies.ResultsIn addition to their significantly reduced standing height compared with non-Pygmies, we find Pygmies to have significantly shorter sitting heights and subischial leg lengths as well as higher sitting/standing height ratios than non-Pygmies. However, while male Pygmies had significantly lower BMI compared with male non-Pygmies, the BMI of females were instead similar. Consistent with prior observations with standing height, sitting height and subischial leg length were strongly correlated with inferred levels of non-Pygmy genetic admixture while BMI was instead weakly correlated, likely reflecting the greater contribution of non-genetic factors to the determination of body weight compared with height. Using 196,725 SNPs on the Illumina Cardio-MetaboChip with genotypes on 358 Pygmy and 169 non-Pygmy individuals together with single-and multi-marker association approaches, we identified a single genomic region and seven genes associated with Pygmy/non-Pygmy categorization as well as 9, 10, 9, and 10 genes associated with standing and sitting height, sitting/standing height ratio, and subischial leg length, respectively. Many of the genes identified have putative functions consistent with a role in determining their associated trait as well as the complex Central African pygmy phenotype.ConclusionsThese findings highlight the potential of modestly sized datasets of Pygmies and non-Pygmies to detect biologically meaningful associations with traits contributing to the Central African pygmy phenotype. Moreover, they provide new insights into the phenotypic and genetic bases of the complex pygmy phenotype and offer new opportunities to facilitate our understanding of its complex evolutionary origins.
Published: 2017
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43. Protein Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease

Author: Jaume Marrugat, Fumihiko Takeuchi, Tanya M. Teslovich, Norihiro Kato, Masa-aki Kawashiri, Jun-Sing Wang, H. Lester Kirchner, Peter S. Braund, Masahiro Nakatochi, Heribert Schunkert, Rosanna Asselta, Danish Saleheen, Daniel R. Lavage, Dustin N. Hartze, Roberto Elosua, Stacey Gabriel, Ingrid B. Borecki, Nilesh J. Samani, Frederick E. Dewey, David J. Carey, Yukihide Momozawa, Chao A. Hsiung, Jerome I. Rotter, Michael F. Murray, Matthew J. Bown, John Danesh, Shane McCarthy, Piera Angelica Merlini, Joseph B. Leader, Namrata Gupta, Tomohiro Katsuya, Gina M. Peloso, Cristen J. Willer, Eitaro Nakashima, Hayato Tada, Gonçalo R. Abecasis, Amit Khera, Pradeep Natarajan, Ken Yamamoto, Derek Klarin, Alistair S. Hall, Connor A. Emdin, Thorsten Kessler, Seyedeh M. Zekavat, Mitsuhiro Yokota, Yii-Der Ida Chen, Akihiro Nomura, Martin Farrall, Hong-Hee Won, Michiaki Kubo, Hugh Watkins, Eric S. Lander, Sekar Kathiresan, James G. Wilson, Ruth McPherson, Masakazu Yamagishi, Kaoru Ito, Adolfo Correa, Jyh-Ming Jimmy Juang, J. Neil Manus, Shih-Yi Lin, Diego Ardissino, Stefano Duga, Daniel J. Rader, Akihiro Inazu, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Male, Human dna, Physiology, Clinical Sciences, cholesteryl ester transfer protein, Coronary Disease, Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Cardiovascular, Article, Truncate, lipids, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cholesterylester transfer protein, Genetics, Humans, Gene, Heart Disease - Coronary Heart Disease, Aged, biology, Chemistry, case-control studies, Genetic Variation, Middle Aged, Atherosclerosis, Coronary heart disease, Cholesterol Ester Transfer Proteins, Heart Disease, 030104 developmental biology, Cardiovascular System & Hematology, Case-Control Studies, Cancer research, biology.protein, lipids (amino acids, peptides, and proteins), Female, Cardiology and Cardiovascular Medicine
Abstract: Rationale : Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We sequenced the exons of the CETP gene in 58 469 participants from 12 case–control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case–control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18–27; P −4 ), lower low-density lipoprotein cholesterol (−12.2 mg/dL; 95% confidence interval, −23 to −0.98; P =0.033), and lower triglycerides (−6.3%; 95% confidence interval, −12 to −0.22; P =0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54–0.90; P =5.1×10 −3 ). Conclusions: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.
Published: 2017

44. Exome-wide association study of plasma lipids in >300,000 individuals

Author: Asif Rasheed, Mary F. Feitosa, Ian J. Deary, Melissa E. Garcia, Danish Saleheen, Christian Gieger, Andrea Maschio, Lia E. Bang, Cliona Molony, Ivan Brandslund, Dan M. Roden, Ian Ford, Paul M. Ridker, Alisa K. Manning, Giorgio Pistis, Anette Varbo, Alexander P. Reiner, Kathleen Stirrups, David C. Liewald, Tim D. Spector, Paul W. Franks, Cristen J. Willer, Daniel I. Chasman, Jean Ferrières, Vilmundur Gudnason, Tapani Ebeling, Neil Poulter, Magdalena Zoledziewska, Elizabeth K. Speliotes, Eleftheria Zeggini, Megan L. Grove, Hua Tang, Stavroula Kanoni, Peter Weeke, Panos Deloukas, Daniel J. Rader, Amit Khera, Serena Sanna, Dorota Pasko, Gina M. Peloso, Charles Kooperberg, Suthesh Sivapalaratnam, Natalie R. van Zuydam, Christian M. Shaffer, Fredrik Karpe, Naveed Sattar, Pieter Muntendam, Ruth J. F. Loos, Eric Boerwinkle, Wei Gao, Mark J. Caulfield, Matt Neville, Sangeetha Somayajula, Olle Melander, Hayato Tada, Jose M. Ordovas, He Zhang, John D. Rioux, Michael Boehnke, Erwin P. Bottinger, Franco Giulianini, Martina Müller-Nurasyid, Stella Trompet, Connor A. Emdin, Andrew P. Morris, Johanne Marie Justesen, Alan R. Tall, Kari Kuulasmaa, Adam S. Butterworth, Marie-Pierre Dubé, Dajiang J. Liu, Paul L. Auer, Jennifer E. Huffman, Usman Baber, John Danesh, Xiao Wang, Anna F. Dominiczak, Jarmo Virtamo, John M. Starr, Ozren Polasek, Gonçalo R. Abecasis, Timo A. Lakka, Stephen S. Rich, Marco M Ferrario, Marju Orho-Melander, Xueling Sim, Dominique Arveiler, Dermot F. Reilly, Torsten Lauritzen, Gudny Eiriksdottir, Marit E. Jørgensen, Anubha Mahajan, Colin N. A. Palmer, Veikko Salomaa, Nicholas J. Wareham, Dewan S. Alam, Anne Tybjærg-Hansen, Ellen M. Schmidt, Y. Eugene Chen, Heather M. Stringham, Bruce M. Psaty, Christie M. Ballantyne, Nan Wang, Joshua C. Bis, Myriam Fornage, Neil S Zheng, Kristian Hveem, Praveen Surendran, Yingchang Lu, Peter S. Sever, James B. Meigs, Heikki A. Koistinen, Charlotta Pisinger, Tibor V. Varga, Yii-Der Ida Chen, Konstantin Strauch, Timothy M. Frayling, Patricia B. Munroe, Albert V. Smith, Ruth Frikke-Schmidt, Lorraine Southam, Frida Renström, Philippe Amouyel, Nicholas G. D. Masca, Alexessander Couto Alves, Xiangfeng Lu, Andres Metspalu, Anne Langsted, Joanna M. M. Howson, Tamara B. Harris, Leif Groop, Chad A. Cowan, Cramer Christensen, Audrey Y. Chu, Markku Laakso, Torben Hansen, Li-An Lin, John C. Chambers, Jonas B. Nielsen, Niels Grarup, Neil R. Robertson, Kiran Musunuru, Joshua S. Weinstock, Morris J. Brown, Jean-Claude Tardif, Gorm B. Jensen, Jerome I. Rotter, Harald Grallert, Yan Zhang, Kerrin S. Small, Nathan O. Stitziel, Fabio Busonero, Jennifer Wessel, Themistocles L. Assimes, Lenore J. Launer, Lars G. Fritsche, Mark O. Goodarzi, Peter W.F. Wilson, Sekar Kathiresan, Philippe M. Frossard, Emanuele Di Angelantonio, Yanhua Zhou, James G. Wilson, Frank Kee, Scott M. Damrauer, Weihua Zhang, Gail Davies, Oluf Pedersen, Sune F. Nielsen, Alanna C. Morrison, Raquel S. Sevilla, Helen R. Warren, Johanna Kuusisto, Hanieh Yaghootkar, Sandosh Padmanabhan, Philip S. Tsao, Caroline Hayward, Tõnu Esko, Ming Xu, Anders Mälarstig, Anne U. Jackson, Eirini Marouli, Jette Bork-Jensen, Robin Young, C.J. O'Donnell, Yong Huo, Melanie Waldenberger, Jaspal S. Kooner, Pekka Mäntyselkä, Marjo-Riitta Järvelin, Santhi K. Ganesh, Annette Peters, L. Adrienne Cupples, Wei Zhou, Derek Klarin, Markus Perola, Francesco Cucca, Allan Linneberg, Mark I. McCarthy, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, J. Wouter Jukema, Valentin Fuster, Claudia Langenberg, Roxana Mehran, Børge G. Nordestgaard, Jaakko Tuomilehto, Reedik Mägi, Blair H. Smith, Johanna Jakobsdottir, Marianne Benn, Kent D. Taylor, Ani Manichaikul, Igor Rudan, Aniruddh P. Patel, Joshua C. Denny, Oddgeir L. Holmen, John M. C. Connell, Robert A. Scott, Haojie Yu, Rajiv Chowdhury, Sehrish Jabeen, Antonella Mulas, Aliki-Eleni Farmaki, Rainer Rauramaa, George Dedoussis, Vascular Medicine, Nielsen, Jonas B [0000-0002-6654-2852], Kathiresan, Sekar [0000-0002-6724-032X], Apollo - University of Cambridge Repository, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: 0301 basic medicine, Exome/genetics, Genome-wide association study, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Charge Diabetes Working Group, Macular Degeneration, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Exome, Macular Degeneration/blood, Genetics & Heredity, Genetic Predisposition to Disease/genetics, CLONAL HEMATOPOIESIS, 11 Medical And Health Sciences, CODING-SEQUENCE VARIANTS, Lipids, Phenotype, CARDIOVASCULAR-DISEASE, VA Million Veteran Program, lipids (amino acids, peptides, and proteins), GOLD Consortium, LOW-FREQUENCY, EPIC-InterAct Consortium, Diabetes Mellitus, Type 2/blood, Life Sciences & Biomedicine, Type 2, medicine.medical_specialty, Genotype, APOBEC-1 COMPLEMENTATION FACTOR, Biology, Lower risk, Article, EPIC-CVD Consortium, GENETIC ARCHITECTURE, 03 medical and health sciences, Coronary Artery Disease/blood, Diabetes mellitus, Internal medicine, Genetics, medicine, Diabetes Mellitus, Journal Article, Lipolysis, Humans, Genetic Predisposition to Disease, Allele, TYROSINE KINASE JAK2, Genetic Association Studies, B MESSENGER-RNA, Science & Technology, MACULAR DEGENERATION, MYELOPROLIFERATIVE DISORDERS, Cholesterol, Lipids/blood, Genetic Variation, 06 Biological Sciences, medicine.disease, cardiovascular diseases, genome wide association studies, Genetic Association Studies/methods, 030104 developmental biology, Endocrinology, chemistry, Diabetes Mellitus, Type 2, TM6SF2, Developmental Biology
Abstract: We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.
Published: 2017
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45. Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans

Author: Yii-Der Ida Chen, Nancy L. Heard-Costa, James G. Wilson, Jeffrey Haessler, Stephanie A. Rosse, Paul L. Auer, Mengmeng Du, Nora Franceschini, Rebecca D. Jackson, Ulrike Peters, Keith R. Curtis, Kari E. North, Deborah A. Nickerson, Guillaume Lettre, Keri L. Monda, Alexander P. Reiner, Cara L. Carty, Shuo Jiao, Christopher S. Carlson, Leslie A. Lange, Stephen S. Rich, Li Hsu, Cristen J. Willer, Jerome I. Rotter, Charles Kooperberg, David Altshuler, and Eric Boerwinkle
Subjects: Adult, Male, Genome-wide association study, Single-nucleotide polymorphism, Biology, White People, Quantitative Trait, Heritable, Gene Frequency, Genetics, Humans, Exome, Molecular Biology, Allele frequency, Alleles, Genetics (clinical), Exome sequencing, Aged, Genetic association, Chromosomes, Human, Pair 13, Association Studies Articles, General Medicine, Middle Aged, Body Height, Black or African American, Minor allele frequency, Genetic Loci, Chromosomes, Human, Pair 5, Female, Imputation (genetics), Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract: Adult body height is a quantitative trait for which genome-wide association studies (GWAS) have identified numerous loci, primarily in European populations. These loci, comprising common variants, explain
Published: 2014
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46. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk

Author: Tom Wilsgaard, Lars J. Vatten, Ellen M. Schmidt, Jin-jin Chen, Oddgeir L. Holmen, Carl G. P. Platou, Gonçalo R. Abecasis, Jifeng Zhang, Subramaniam Pennathur, Inger Njølstad, He-Ming Zhang, Yanhong Guo, Arnulf Langhammer, Ji Zhang, Wei-Wei Zhou, Kristian Hveem, Maja-Lisa Løchen, Y. Eugene Chen, Santhi K. Ganesh, Michael Boehnke, Frank Skorpen, Daniel H. Hovelson, Håvard Dalen, Ellisiv B. Mathiesen, Cristen J. Willer, and Yanbo Fan
Subjects: Genetics, Genetic Variation, Membrane Proteins, Genome-wide association study, Locus (genetics), Biology, Lipids, Article, genetics research, myocardial infarction, genome-wide association studies, Genetic variation, Genotype, Animals, Humans, Gene, Exome, TM6SF2, Common disease-common variant
Abstract: Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify new genes influencing lipid traits, fine map known lipid loci and evaluate whether low-frequency variants with large effects exist for these traits. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians and identified ten loci with coding variants associated with a lipid trait (P < 5 × 10−8). One variant in TM6SF2 (encoding p.Glu167Lys), residing in a known genome-wide association study locus for lipid traits, influences total cholesterol levels and is associated with myocardial infarction. Transient TM6SF2 overexpression or knockdown of Tm6sf2 in mice alters serum lipid profiles, consistent with the association observed in humans, identifying TM6SF2 as a functional gene within a locus previously known as NCAN-CILP2-PBX4 or 19p13. This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.
Published: 2014
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47. Common variants associated with plasma triglycerides and risk for coronary artery disease

Author: Richard S. Cooper, Angela Döring, Cisca Wijmenga, Jerome I. Rotter, Linda S. Adair, Tõnu Esko, Jennifer L. Bragg-Gresham, Danish Saleheen, Narisu Narisu, Xiaohui Li, Kathleen Stirrups, Ulf de Faire, Nicholas G. Martin, Dmitry Shungin, Peter Vollenweider, Yii-Der Ida Chen, Dharambir K. Sanghera, George Dedoussis, Toshiko Tanaka, Manjinder S. Sandhu, Anne U. Jackson, Nancy L. Pedersen, Maria Dimitriou, Shih-Yi Lin, David P. Strachan, Isleifur Olafsson, Ruth J. F. Loos, Kay-Tee Khaw, Antero Kesäniemi, Rainer Rauramaa, Wendy L. McArdle, Gonneke Willemsen, Dena G. Hernandez, May E. Montasser, Amy J. Swift, Colin A. McKenzie, Aaron Isaacs, Latonya F. Been, Leif Groop, Massimo Mangino, Martina Müller-Nurasyid, Karen L. Mohlke, Ci Song, Sailaja Vedantam, Anna-Liisa Hartikainen, Lori L. Bonnycastle, Ilja M. Nolte, Jaakko Kaprio, Anneli Pouta, Unnur Thorsteinsdottir, Paul Elliott, Muredach P. Reilly, Jean Ferrières, Daniel J. Rader, Elizabeth H. Young, Jaspal S. Kooner, Leena Moilanen, Markku Laakso, Albert Hofman, Kelly A. Volcik, Sekar Kathiresan, Tamara B. Harris, Eric Kim, Aimo Ruokonen, Andrea Ganna, Serena Sanna, John J.P. Kastelein, Martha L. Gravito, Ronald M. Krauss, Ken K. Ong, Paul M. Ridker, Kristian Hveem, Ayse Demirkan, Alena Stančáková, Pierre Meneton, Thomas Quertermous, John Danesh, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Christopher J. Groves, Jaakko Tuomilehto, Michael Boehnke, Jose M. Ordovas, Alan B. Feranil, Chao A. Hsiung, Wayne Huey-Herng Sheu, Igor Rudan, Christa Meisinger, Rebecca N. Nsubuga, Bruna Gigante, Inger Njølstad, Göran Hallmans, Aroon D. Hingorani, Jouko Saramies, Deepti Gurdasani, Fernando Rivadeneira, Andres Metspalu, Stephen E. Epstein, Gonçalo R. Abecasis, Braxton D. Mitchell, Devin Absher, Marcus E. Kleber, Sonia Shah, Pierre Fontanillas, Jeffrey R. O'Connell, Louise A. Donnelly, Jing Hua Zhao, Martin L. Buchkovich, Francis S. Collins, Gabrielle Müller, Matti Uusitupa, Evelin Mihailov, Nicholas J. Wareham, Andrew A. Hicks, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Jaana Lindström, Mark I. McCarthy, Evita G. Van Den Herik, Kirsten Ohm Kyvik, Vilmundur Gudnason, Jackie F. Price, Joel N. Hirschhorn, Winfried März, Aravinda Chakravarti, Pontiano Kaleebu, James F. Wilson, Lindsay L. Waite, Leo-Pekka Lyytikäinen, Sebanti Sengupta, Mika Kivimäki, David Altshuler, Hilma Holm, Rona J. Strawbridge, Harald Grallert, Ramaiah Nagaraja, Laurence Tiret, G. Kees Hovingh, Meena Kumari, Nilesh J. Samani, Daniel F. Freitag, Nelson B. Freimer, Thomas Illig, Panos Deloukas, Bernhard O. Boehm, Nicholas W.J. Wainwright, Mark J. Daly, Mika Kähönen, Michel Burnier, Norman Klopp, L. Adrienne Cupples, Aarno Palotie, Markus Perola, Bamidele O. Tayo, Timo A. Lakka, Matthew Jones, Sarah H. Wild, Patricia B. Munroe, Antti Jula, François Mach, Peter J. Koudstaal, Pirjo Komulainen, Eric Boerwinkle, L. Joost van Pelt, Veikko Salomaa, Ann-Kristin Petersen, Ida Surakka, Andrew Wong, Caroline Hayward, Chi Gao, Cristen J. Willer, Stephen S. Rich, Yi Jen Hung, Peter P. Pramstaller, Diana Kuh, Ron Do, Dominique Arveiler, Mark O. Goodarzi, Ross M. Fraser, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Mary Susan Burnett, Patrik K. E. Magnusson, John C. Chambers, Benjamin M. Neale, Peter Schwarz, Jennifer L. Bolton, Murielle Bochud, Heleen M. den Hertog, Christian Gieger, Cristina Pomilla, Teresa Ferreira, Lars Wallentin, Richa Saxena, André G. Uitterlinden, Kaisa Silander, Ying Wu, Bruce M. Psaty, Jian'an Luan, Hsing-Yi Chang, Jin Chen, Daniel I. Chasman, Ulf Gyllensten, Kari Stefansson, Kauko Heikkilä, Tom Wilsgaard, Alan R. Shuldiner, Carlos Iribarren, Stavroula Kanoni, John Whitfield, Gershim Asiki, Marika Kaakinen, Georg Ehret, Elina Hyppönen, Claudia Langenberg, Gina M. Peloso, Cecilia M. Lindgren, Carlo Sidore, Gudmundur I. Eyjolfsson, Cameron D. Palmer, Jacques S. Beckmann, Hubert Scharnagl, Tanya M. Teslovich, Mary F. Feitosa, Terho Lehtimäki, Steve E. Humphries, Chris Power, Benjamin F. Voight, Stefania Bandinelli, Andrew D. Morris, Gudmar Thorleifsson, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Themistocles L. Assimes, Pascal Bovet, Luigi Ferrucci, Johannes Kettunen, Inês Barroso, Franklyn I. Bennett, Stefan Gustafsson, Paolo Brambilla, Theodore Papamarkou, Elena Tremoli, Janet Seeley, Alex S. F. Doney, Johanna Kuusisto, Giancarlo Cesana, Bruce H. R. Wolffenbuttel, Lars Lind, Stefan R. Bornstein, Åsa Johansson, Anders Hamsten, Marjo-Riitta Järvelin, Krista Fischer, Agneta Siegbahn, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, Do, Ron, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Hyppönen, Elina, Kathiresan, Sekar, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Do, R, Willer, C, Schmidt, E, Sengupta, S, Gao, C, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stančáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Altshuler, D, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Mohlke, K, Ingelsson, E, Abecasis, G, Daly, M, Neale, B, and Kathiresan, S
Subjects: Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Heart disease, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, ISCHEMIC-HEART-DISEASE, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Polymorphism (computer science), Risk Factors, High-density-lipoprotein, Genetic epidemiology, 11 Medical and Health Sciences, Genetics & Heredity, 0303 health sciences, Cholesterol, HDL/blood, Cholesterol levels, Loci, Contribute, Single Nucleotide, LDL/blood, Triglycerides/blood, Cholesterol, Cholesterol, LDL/blood, HDL/blood, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Human, medicine.medical_specialty, TYPE-2 DIABETES-MELLITUS, Biology, Polymorphism, Single Nucleotide, Article, HIGH-DENSITY-LIPOPROTEIN ISCHEMIC-HEART-DISEASE TYPE-2 DIABETES-MELLITUS MENDELIAN RANDOMIZATION CARDIOVASCULAR-DISEASE GENETIC EPIDEMIOLOGY CHOLESTEROL LEVELS LOCI CONTRIBUTE THERAPY, 03 medical and health sciences, Coronary Artery Disease/blood, SDG 3 - Good Health and Well-being, Cardiovascular-disease, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Polymorphism, plasma, Triglycerides, 030304 developmental biology, Science & Technology, Risk Factor, Cholesterol, HDL, Biological Transport, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, Heart-disease, lipoproteins, Endocrinology, chemistry, Therapy, Developmental Biology
Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved.
Published: 2013
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48. Discovery and refinement of loci associated with lipid levels

Author: Benjamin F. Voight, Stefania Bandinelli, Pascal Bovet, Latonya F. Been, Ci Song, Luigi Ferrucci, Johannes Kettunen, Andrew D. Morris, Mary Susan Burnett, Ronald M. Krauss, Igor Rudan, Heleen M. den Hertog, Stavroula Kanoni, G. Kees Hovingh, Elina Hyppönen, Kauko Heikkilä, Richard S. Cooper, Daniel I. Chasman, Bruna Gigante, Stefan Gustafsson, Jian'an Luan, Sarah H. Wild, Patricia B. Munroe, Göran Hallmans, Jeffrey R. O'Connell, Danish Saleheen, Aarno Palotie, Leena Moilanen, Jerome I. Rotter, Caroline Hayward, Jennifer L. Bragg-Gresham, Nicholas G. Martin, Claudia Langenberg, George Dedoussis, Carlo Sidore, Ulf Gyllensten, Marika Kaakinen, Jing Hua Zhao, Aimo Ruokonen, Diana Kuh, Maria Dimitriou, Shih-Yi Lin, Gina M. Peloso, Marcus E. Kleber, Christopher J. Groves, Alena Stančáková, Michel Burnier, Patrik K. E. Magnusson, John C. Chambers, Giancarlo Cesana, Francis S. Collins, Gabrielle Müller, Angela Döring, Colin A. McKenzie, Paul Elliott, Lars Lind, Vilmundur Gudnason, Dharambir K. Sanghera, Jean Ferrières, Toshiko Tanaka, Stefan R. Bornstein, Gershim Asiki, Jacques S. Beckmann, Anneli Pouta, Timo A. Lakka, Daniel J. Rader, Elizabeth H. Young, Kelly A. Volcik, Dena G. Hernandez, Ann-Kristin Petersen, Kristian Hveem, Amy J. Swift, Murielle Bochud, Pierre Meneton, Paul M. Ridker, Kathleen Stirrups, Stephen S. Rich, Isleifur Olafsson, Ruth J. F. Loos, Serena Sanna, Markus Perola, Meena Kumari, Cameron D. Palmer, Carlos Iribarren, Nancy L. Pedersen, Mark O. Goodarzi, Panos Deloukas, Norman Klopp, Cristina Pomilla, Stephen E. Epstein, Antti Jula, Themistocles L. Assimes, Martina Müller-Nurasyid, Marjo-Riitta Järvelin, Chao A. Hsiung, Sonia Shah, Christian Gieger, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Nicholas J. Wareham, Krista Fischer, Wendy L. McArdle, Linda S. Adair, Kay-Tee Khaw, Bruce M. Psaty, André G. Uitterlinden, Aaron Isaacs, Tõnu Esko, Jennifer L. Bolton, Rebecca N. Nsubuga, Eric Boerwinkle, L. Joost van Pelt, Jouko Saramies, François Mach, Pierre Fontanillas, Teresa Ferreira, Lars Wallentin, Michael Boehnke, Christa Meisinger, Wayne Huey-Herng Sheu, Gonçalo R. Abecasis, Inês Barroso, Franklyn I. Bennett, Dmitry Shungin, Jaakko Kaprio, Kirsten Ohm Kyvik, Deepti Gurdasani, Anne U. Jackson, Paolo Brambilla, Georg Ehret, Cecilia M. Lindgren, Fernando Rivadeneira, Theodore Papamarkou, Jaakko Tuomilehto, Cristen J. Willer, Martin L. Buchkovich, Antero Kesäniemi, Hubert Scharnagl, Xiaohui Li, Elena Tremoli, Nelson B. Freimer, Mika Kähönen, Ron Do, Karen L. Mohlke, Thomas Illig, Gudmar Thorleifsson, Peter J. Koudstaal, Andres Metspalu, Ulf de Faire, Dominique Arveiler, Harald Grallert, Jaana Lindström, Laurence Tiret, Jaspal S. Kooner, Braxton D. Mitchell, Sebanti Sengupta, Gonneke Willemsen, Anna-Liisa Hartikainen, Terho Lehtimäki, Steve E. Humphries, Peter Schwarz, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Tom Wilsgaard, Janet Seeley, Alex S. F. Doney, Alan R. Shuldiner, John Whitfield, Markku Laakso, Peter Vollenweider, Gudmundur I. Eyjolfsson, Winfried März, Mika Kivimäki, Ying Wu, Johanna Kuusisto, Andrew A. Hicks, Bruce H. R. Wolffenbuttel, May E. Montasser, Bamidele O. Tayo, Unnur Thorsteinsdottir, Muredach P. Reilly, Leo-Pekka Lyytikäinen, Eric Kim, John Danesh, Ida Surakka, Åsa Johansson, Anders Hamsten, Thomas Quertermous, Hsing-Yi Chang, Jin Chen, Agneta Siegbahn, Narisu Narisu, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, Sekar Kathiresan, Manjinder S. Sandhu, Leif Groop, Jose M. Ordovas, Alan B. Feranil, Evelin Mihailov, Hilma Holm, Pontiano Kaleebu, Lindsay L. Waite, Ramaiah Nagaraja, Andrew Wong, Rona J. Strawbridge, David P. Strachan, Yii-Der Ida Chen, Tamara B. Harris, Jackie F. Price, Aravinda Chakravarti, Veikko Salomaa, Sailaja Vedantam, Albert Hofman, Devin Absher, Ross M. Fraser, Kaisa Silander, Pirjo Komulainen, Yi Jen Hung, Peter P. Pramstaller, Kari Stefansson, Aroon D. Hingorani, Tanya M. Teslovich, Matti Uusitupa, L. Adrienne Cupples, Cisca Wijmenga, Lori L. Bonnycastle, Ilja M. Nolte, Andrea Ganna, Ken K. Ong, Inger Njølstad, Bernhard O. Boehm, Nicholas W.J. Wainwright, Richa Saxena, Rainer Rauramaa, Louise A. Donnelly, James F. Wilson, Matthew Jones, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Massimo Mangino, John J.P. Kastelein, Martha L. Gravito, Mark I. McCarthy, Evita G. Van Den Herik, Joel N. Hirschhorn, Nilesh J. Samani, Daniel F. Freitag, Ayse Demirkan, Mary F. Feitosa, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Chris Power, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Willer, C, Schmidt, E, Sengupta, S, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Do, R, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stancáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Kathiresan, S, Mohlke, K, Ingelsson, E, Abecasis, G, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Ehret, Georg Benedikt, Mach, François, Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, National Institute for Health Research, Global Lipids Genetics Consortium, Willer, Cristen, Sengupta, Sebanti, Peloso, Gina, Hypponen, Elina Tuulikki, and Abecasis, Gonçalo R
Subjects: Netherlands Twin Register (NTR), HOMEOSTASIS, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Blood lipids, Genome-wide association study, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, European Continental Ancestry Group/genetics, triglycerides, IDENTIFIES 13, 11 Medical and Health Sciences, African Continental Ancestry Group, 2. Zero hunger, Genetics, Genetics & Heredity, ddc:616, RISK, 0303 health sciences, Cholesterol, HDL/blood, PLASMA, Global Lipids Genetics Consortium, Cholesterol, HDL/blood/genetics, Lipid, Lipids, 3. Good health, LDL/blood, Triglycerides/blood, Lipids/blood/genetics, Cholesterol, Cholesterol, LDL/blood, DENSITY-LIPOPROTEIN CHOLESTEROL, CARDIOVASCULAR-DISEASE, HDL/blood, CORONARY-ARTERY-DISEASE, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, coronary artery disease, TRAITS, Human, Coronary Artery Disease/blood/genetics, Asian Continental Ancestry Group, Genotype, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Black People, HEART-DISEASE, Biology, Article, White People, lipids, 03 medical and health sciences, Coronary Artery Disease/blood, CORONARY-ARTERY-DISEASE DENSITY-LIPOPROTEIN CHOLESTEROL GENOME-WIDE ASSOCIATION HEART-DISEASE CARDIOVASCULAR-DISEASE SUSCEPTIBILITY LOCI IDENTIFIES 13 RISK GENE METAANALYSIS, Triglycerides/blood/genetics, Asian People, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Humans, Asian Continental Ancestry Group/genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Genotyping, Triglycerides, METAANALYSIS, 030304 developmental biology, Science & Technology, Lipids/blood, Cholesterol, HDL, cholesterol, African Continental Ancestry Group/genetics, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, GENE, chemistry, Cholesterol, LDL/blood/genetics, Lipoprotein, Developmental Biology, Genome-Wide Association Study
Abstract: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10 -8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research. © 2013 Nature America, Inc. All rights reserved.
Published: 2013
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49. Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease

Author: Qiao Fan, Ying Wu, Tien Yin Wong, Jirong Long, Xiuqing Guo, Dongfeng Gu, Gonçalo R. Abecasis, Yan Zhang, Yii-Der Ida Chen, Feijie Wang, Meian He, Sekar Kathiresan, Pak C. Sham, Penny Gordon-Larsen, Cassandra N. Spracklen, Karen S.L. Lam, Santhi K. Ganesh, Xiao-Ou Shu, Wei Gao, Alan B. Feranil, Wei Zheng, Shufa Du, Gina M. Peloso, Jonas B. Nielsen, Rajkumar Dorajoo, Wei Zhou, Y. Eugene Chen, Shi Jinxiu, Shufeng Chen, Stacey S. Cherny, Cristen J. Willer, Jianjun Liu, Xiangfeng Lu, Kuai Yu, Yiqin Wang, Wei Huang, Chiea Chuen Khor, Wanting Zhao, Yu-Tang Gao, Qiuyin Cai, Clara S. Tang, Jun Li, Hung-Fat Tse, Huaixing Li, Xueli Yang, Xu Lin, Jianfeng Huang, Chloe Y Y Cheung, Tangchun Wu, Ming Xu, Ching-Yu Cheng, Wayne H-H Sheu, Dajiang J. Liu, Kristian Hveem, Karen L. Mohlke, Liang Sun, Laiyuan Wang, Yang Chen, Lars G. Fritsche, Linda S. Adair, Xuezhen Liu, Yong Huo, Yao Hu, He Zhang, Rohit Varma, Zengnan Mo, and E. Shyong Tai
Subjects: 0301 basic medicine, Genotype, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, White People, Article, 03 medical and health sciences, 0302 clinical medicine, Asian People, Gene Frequency, Genetic variation, Genetics, Humans, Exome, Genetic Predisposition to Disease, Gene, Allele frequency, Genetic association, Asia, Eastern, Genetic Variation, Lipid metabolism, Lipid Metabolism, Lipids, Europe, 030104 developmental biology, Genome-Wide Association Study
Abstract: Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.
Published: 2016

50. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Author: Angelo Scuteri, Chris Wallace, Rachel Hackett, Sonja I. Berndt, Richard B. Hayes, Peter Vollenweider, Susan M. Ring, Lauren Gianniny, Alistair S. Hall, Christopher J. Gillson, Karani Santhanakrishnan Vimaleswaran, Karol Estrada, Thomas Meitinger, Kay-Tee Khaw, Nicholas J. Timpson, Willem H. Ouwehand, Cristen J. Willer, Andy R Ness, Peter S. Chines, Wendy L. McArdle, I. Sadaf Farooqi, Eleftheria Zeggini, Jouko Saramies, Amanda J. Bennett, Matthew A. Sims, Richard M. Watanabe, David M. Evans, Patricia B. Munroe, Toshiko Tanaka, Francis S. Collins, Peter Kraft, Morris Brown, Inês Barroso, Sheila Bingham, John M. C. Connell, Jian'an Luan, Pekka Jousilahti, Amanda F. Elliott, Lachlan J. M. Coin, Parimal Deodhar, Kijoung Song, Ruth J. F. Loos, Eleanor Wheeler, George Davey Smith, Kate Northstone, Joshua C. Randall, Claudia Lamina, André G. Uitterlinden, Dawn M. Waterworth, Tim D. Spector, Robert Luben, Veikko Salomaa, Vincent Mooser, Candace Guiducci, Andrew T. Hattersley, Guillaume Lettre, Guangju Zhai, Gonçalo R. Abecasis, Jaana Laitinen, Cyrus Cooper, David J. Hunter, Noël P. Burtt, Timo T. Valle, Carolin Purmann, Narisu Narisu, Lori L. Bonnycastle, Steven A. McCarroll, Christian Gieger, Albert Hofman, Laura J. Scott, Iris M. Heid, Lu Qi, Kevin B. Jacobs, Toby Johnson, Cornelia M. van Duijn, David Altshuler, David Hadley, Marjo-Riitta Järvelin, Johannes Hebebrand, Stephen J. Chanock, Stephen O'Rahilly, Jaakko Tuomilehto, Cecilia M. Lindgren, Y. C. Loraine Tung, Panagiotis Deloukas, Manjinder S. Sandhu, H-Erich Wichmann, Antonella Mulas, Matthew G. Rees, Jack M. Guralnik, Elaine M. Dennison, Timothy M. Frayling, David P. Strachan, Jonathan Stephens, Inga Prokopenko, Mikko Kuokkanen, Shengxu Li, Leif Groop, Jing Hua Zhao, Paul Elliott, David Schlessinger, Ken K. Ong, Peter Almgren, Massimo Mangino, Manuela Uda, Zorica Jovanovic, Karen L. Mohlke, Leena Peltonen, Michael N. Weedon, Elizabeth K. Speliotes, Markku Laakso, Bo Isomaa, Serena Sanna, Mark J. Caulfield, Gérard Waeber, Martin Ridderstråle, Luigi Ferrucci, Anne U. Jackson, Suzanne Stevens, Aimo Ruokonen, Jacqueline C. M. Witteman, Nicole Soranzo, Kaisa Silander, Mark I. McCarthy, Joel N. Hirschhorn, Nilesh J. Samani, Frank B. Hu, Michael R. Erdos, Paul Scheet, Leonie C. Jacobs, Rosa Maria Roccasecca, Heather M. Stringham, Helen N. Lyon, Konstantinos A. Papadakis, Aki S. Havulinna, Michael Boehnke, Richard N. Bergman, Nicholas J. Wareham, M. Carola Zillikens, Nicholas A. Watkins, Tiinamaija Tuomi, Fernando Rivadeneira, Noha Lim, Edward G. Lakatta, and Johanna Kuusisto
Subjects: Central Nervous System, medicine.medical_specialty, Quantitative Trait Loci, Medizin, Gene Dosage, 030209 endocrinology & metabolism, Genome-wide association study, Locus (genetics), Biology, FTO gene, Polymorphism, Single Nucleotide, Article, Body Mass Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Quantitative Trait, Heritable, SH2B1, Meta-Analysis as Topic, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Obesity, Alleles, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Neuronal growth regulator 1, Anthropometry, Genetics of obesity, Body Weight, 3. Good health, Endocrinology, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Genome-Wide Association Study, Colaus Study, Body mass index
Abstract: Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10⁻⁸): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity. © 2009 Nature America, Inc. All rights reserved.
Published: 2016
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