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101. Polygenic Risk Score Identifies Patients at Increased Risk for Abdominal Aortic Aneurysm and May Benefit from Ultrasound Screening

Author: Salvatore T. Scali, Pradeep Natarajan, Yan V. Sun, Daniel J. Rader, Themistocles L. Assimes, Julie Lynch, Girish N. Nadkarni, Ozan Dikilitas, Cristen J. Willer, Philip S. Tsao, Michael G. Levin, Derek Klarin, Renae Judy, Scott A. Berceli, Sekar Kathiresan, Iftikhar J. Kullo, Peter W.F. Wilson, Ishan Paranjpe, Scott M. Damrauer, and Brooke N. Wolford
Subjects: medicine.medical_specialty, Increased risk, Ultrasound screening, business.industry, RC666-701, Internal medicine, medicine, Cardiology, Diseases of the circulatory (Cardiovascular) system, Polygenic risk score, business, medicine.disease, Abdominal aortic aneurysm
Published: 2020
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102. Higher admission rates and in-hospital mortality for acute type A aortic dissection during Influenza season: a single center experience

Author: Cristen J. Willer, Elizabeth L. Norton, James B. Froehlich, Marion A. Hofmann Bowman, Michael Deeb, Carmel Ashur, Linda Farhat, Bo Yang, Karen M. Kim, David J. Pinsky, Himanshu J. Patel, Anna Conlon, Kim A. Eagle, and Shinichi Fukuhara
Subjects: Male, Risk, medicine.medical_specialty, Michigan, Future studies, Time Factors, Influenza vaccine, Cardiology, lcsh:Medicine, Influenza season, 030204 cardiovascular system & hematology, Single Center, Article, Disease Outbreaks, 03 medical and health sciences, 0302 clinical medicine, Aneurysm, Patient Admission, Influenza, Human, Medicine, Humans, 030212 general & internal medicine, Hospital Mortality, lcsh:Science, Aged, Aortic dissection, Multidisciplinary, In hospital mortality, business.industry, lcsh:R, Middle Aged, medicine.disease, Aortic Aneurysm, Aortic Dissection, Risk factors, Acute type, Emergency medicine, Acute Disease, lcsh:Q, Female, Disease Susceptibility, Seasons, business
Abstract: Triggering events for acute aortic dissections are incompletely understood. We sought to investigate whether there is an association between admission for acute type A aortic dissection (ATAAD) to the University of Michigan Medical Center and the reported annual influenza activity by the Michigan Department of Health and Human Services. From 1996–2019 we had 758 patients admitted for ATAAD with 3.1 admissions per month during November-March and 2.5 admissions per month during April-October (p = 0.01). Influenza reporting data by the Michigan Department of Health and Human Services became available in 2009. ATAAD admissions for the period 2009–2019 (n = 455) were 4.8 cases/month during peak influenza months compared to 3.5 cases/month during non-peak influenza months (p = 0.001). ATAAD patients admitted during influenza season had increased in-hospital mortality (11.0% vs. 5.8%, p = 0.024) and increased 30-day mortality (9.7 vs. 5.4%, p = 0.048). The results point to higher admission rates for ATAAD during months with above average influenza rates. Future studies need to investigate whether influenza virus infection affects susceptibility for aortic dissection, and whether this risk can be attenuated with the annual influenza vaccine in this patient population.
Published: 2019

103. Aortic progression and reintervention in patients with pathogenic variants after a thoracic aortic dissection

Author: Bo Yang, Sarah E. Graham, Xiaoting Wu, Whitney E. Hornsby, Cristen J. Willer, Elizabeth L. Norton, and Brooke N. Wolford
Subjects: Pulmonary and Respiratory Medicine, Marfan syndrome, Adult, Male, Reoperation, medicine.medical_specialty, Time Factors, 030204 cardiovascular system & hematology, National Death Index, Loeys–Dietz syndrome, Gastroenterology, Risk Assessment, Article, 03 medical and health sciences, Blood Vessel Prosthesis Implantation, 0302 clinical medicine, Postoperative Complications, Risk Factors, Internal medicine, medicine, Humans, Exome sequencing, Aorta, Aged, Retrospective Studies, Aortic dissection, Aortic Aneurysm, Thoracic, business.industry, Medical record, Dissection, Hazard ratio, Middle Aged, medicine.disease, Aortic Dissection, Treatment Outcome, 030228 respiratory system, Cohort, Disease Progression, Surgery, Female, Cardiology and Cardiovascular Medicine, business
Abstract: OBJECTIVE: To evaluate aortic disease progression and reintervention following an initial thoracic aortic dissection in pathogenic variant carriers. METHODS: Of 175 participants diagnosed with thoracic aortic dissection, 31 had a pathogenic variant (pathogenic group) across 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2) identified by whole exome sequencing. Those with benign or normal variants (benign/normal group, n=144) comprised the control group. Clinical data was collected through medical record review (1985-2018) and supplemented with the National Death Index database (December 2018). RESULTS: The entire cohort (n=175) consisted of 108 type A aortic dissections (TAAD) and 67 type B aortic dissections, similarly distributed between groups. The pathogenic group was significantly younger (43- vs. 56-years-old, p
Published: 2019

104. Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

Author: Karen Kim, Linda Farhat, Whitney E. Hornsby, Brooke N. Wolford, Anisa Driscoll, Himanshu J. Patel, Y. Eugene Chen, Chad M. Brummett, Xiaoting Wu, Jennifer McNamara, Nicholas J. Douville, Ellen M. Schmidt, Dongchuan Guo, G. Michael Deeb, Maoxuan Lin, Cristen J. Willer, Wei Zhou, Elizabeth L. Norton, Michael R. Mathis, Santhi K. Ganesh, Jacob O. Kitzman, Dianna M. Milewicz, Bo Yang, and Kim A. Eagle
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, Fibrillin-1, 030204 cardiovascular system & hematology, Aortic disease, Article, Protein-Lysine 6-Oxidase, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, Exome Sequencing, medicine, Humans, Genetic Testing, Smad3 Protein, Exome sequencing, Aged, Cyclic GMP-Dependent Protein Kinase Type I, Aged, 80 and over, Routine screening, Aortic Aneurysm, Thoracic, business.industry, Genetic variants, Receptor, Transforming Growth Factor-beta Type II, General Medicine, Middle Aged, Pedigree, Aortic Dissection, 030104 developmental biology, Collagen Type III, Case-Control Studies, Hypertension, Thoracic aortic dissection, Female, Radiology, business
Abstract: Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset
Published: 2019

105. Mendelian Randomization Analysis Dissects the Relationship between NAFLD, T2D, and Obesity and Provides Implications to Precision Medicine

Author: Wanqing Liu, Y. Eugene Chen, Yang Zhang, Roger Pique-Regi, Sarah E. Graham, Cristen J. Willer, Xiaocheng Charlie Dong, and Zhipeng Liu
Subjects: 0303 health sciences, business.industry, Fatty liver, nutritional and metabolic diseases, 030209 endocrinology & metabolism, Genome-wide association study, Mendelian Randomization Analysis, Disease, Type 2 diabetes, medicine.disease, Bioinformatics, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, medicine, Risk factor, business, 030304 developmental biology, TM6SF2
Abstract: BackgroundNon-alcoholic fatty liver disease (NAFLD) is epidemiologically correlated with both type 2 diabetes (T2D) and obesity. However, the causal inter-relationships among the three diseases have not been completely investigated.AimWe aim to explore the causal relationships among the three diseases.Design and methodsWe performed a genome-wide association study (GWAS) on fatty liver disease in ∼400,000 UK BioBank samples. Using this data as well as the largest-to-date publicly available summary-level GWAS data, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis. This analysis tested the causal inter-relationship between NAFLD, T2D, and obesity, as well as the association between genetically driven NAFLD (with two well-established SNPs at the PNPLA3 and TM6SF2 loci) and glycemic and lipidemic traits, respectively. Transgenic mice expressing the human PNPLA3 I148I (TghPNPLA3-I148I) and PNPLA3 I148M (TghPNPLA3-I148M) isoforms were used to further validate the causal effects.ResultsWe found that genetically instrumented hepatic steatosis significantly increased the risk for T2D (OR=1.3, 95% CI: [1.2, 1.4],p=8.3e-14) but not the intermediate glycemic phenotypes at the Bonferroni-adjusted level of significance (pp=1.3e-4), but an increased risk for WHRadjBMI (Waist-Hip Ratio adjusted for BMI) (β=0.039 SD, 95%CI: [0.023, 0.054],p=8.2e-7), as well as a decreased level for total cholesterol (β=-0.084 SD, 95%CI [−0.13, −0.036],p=6.8e-4), but not triglycerides (β=0.02 SD, 95%CI [−0.023, 0.062],p=0.36). The reverse MR analyses suggested that genetically driven T2D (OR=1.1, 95% CI: [1.0, 1.2],p=1.7e-3), BMI (OR=2.3, 95% CI: [2.0, 2.7],p=1.4e-25) and WHRadjBMI (OR=1.5, 95% CI: [1.3, 1.8],p=1.1e-6) causally increase the NAFLD risk. In the animal study, as compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed higher fasting glucose level and reduced glucose clearance. Meanwhile, the TghPNPLA3-I148M mice demonstrated a reduced body weight, increased central to peripheral fat ratio, decreased circulating total cholesterol as compared to the TghPNPLA3-I148I controls.ConclusionThis large-scale bidirectional MR study suggests that lifelong, genetically driven NAFLD is a causal risk factor for T2D (hence potentially a “NAFLD-driven T2D” subtype) and central obesity (or “NAFLD-driven obesity” subtype), but protects against overall obesity; while genetically driven T2D, obesity, and central obesity also causally increase the risk of NAFLD, hence a “metabolic NAFLD”. This causal relationship revealed new insights into disease subtypes and provided novel hypotheses for precision treatment or prevention for the three diseases.
Published: 2019
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106. Gait speed is a preoperative indicator of postoperative events after elective proximal aortic surgery

Author: Xiaoting Wu, Bo Yang, Whitney E. Hornsby, Jonathan Afilalo, Cristen J. Willer, Scott L. Hummell, Elizabeth L. Norton, Richard L. Prager, and Reilly D. Hobbs
Subjects: Pulmonary and Respiratory Medicine, Aortic arch, Male, medicine.medical_specialty, Time Factors, medicine.medical_treatment, 030204 cardiovascular system & hematology, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, Risk Factors, medicine.artery, Ascending aorta, medicine, Humans, Hospital Mortality, Mobility Limitation, Geriatric Assessment, Aorta, Aged, Retrospective Studies, Rehabilitation, Frailty, business.industry, EuroSCORE, Odds ratio, Middle Aged, Respiration, Artificial, Confidence interval, Patient Discharge, Surgery, Walking Speed, Functional Status, Treatment Outcome, 030228 respiratory system, Median sternotomy, Elective Surgical Procedures, Population study, Female, Cardiology and Cardiovascular Medicine, business, Vascular Surgical Procedures
Abstract: The study objective was to evaluate whether 5-m gait speed, an established marker of frailty, is associated with postoperative events after elective proximal aortic surgery.We performed a retrospective review of 435 patients aged more than 60 years who underwent elective proximal aortic surgery, defined as surgery on the aortic root, ascending aorta, or aortic arch through median sternotomy. Patients completed a 5-m gait speed test within 30 days before surgery. We evaluated the association between categoric (slow, ≤0.83 m/s and normal,0.83 m/s) and continuous gait speed and the likelihood of experiencing the composite outcome before and after adjustment for European System for Cardiac Operative Risk Evaluation II. The composite outcome included in-hospital mortality, renal failure, prolonged ventilation, and discharge location. Secondary outcomes were 1-year mortality and 5-year survival.Of the study population, 30.3% (132/435) were categorized as slow. Slow walkers were significantly more likely to have in-hospital mortality, prolonged ventilation, and renal failure, and were less likely to be discharged home (all P .05). The composite outcome was 2 times more likely to occur for slow walkers (gait speed categoric adjusted odds ratio, 2.08; 95% confidence interval, 1.27-3.40; P = .004). Moreover, a unit (1 m/s) increase in gait speed (continuous) was associated with 73% lower risk of experiencing the composite outcome (odds ratio, 0.27; 95% confidence interval, 0.11-0.68; P = .006).Slow gait speed is a preoperative indicator of risk for postoperative events after elective proximal aortic surgery. Gait speed may be an important tool to complement existing operative risk models, and its application may identify patients who may benefit from presurgical and postsurgical rehabilitation.
Published: 2019

107. 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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108. Loss-of-function genomic variants with impact on liver-related blood traits highlight potential therapeutic targets for cardiovascular disease

Author: Gregory J.M. Zajac, Jerome I. Rotter, Rasika A. Mathias, Vivek Rai, David Schlessinger, Tanmoy Roychowdhury, Yuhao Liu, Kathleen C. Barnes, Maiken Elvestad Gabrielsen, John Blangero, Russell P. Tracy, Xiuqing Guo, Albert V. Smith, Mari Løset, Luis Villacorta, Anita Pandit, Xingnan Li, Kent D. Taylor, Anne Heidi Skogholt, Seunggeun Lee, Brooke N. Wolford, Allison E. Ashley-Koch, Scott T. Weiss, Yingze Zhang, Akua Acheampong, Seung Hoan Choi, Steven A. Lubitz, Ketian Yu, Ren-Hua Chung, Jill M. Johnsen, Seyed Mehdi Nouraie, Lars G. Fritsche, Lisa R. Yanek, Yii Der Chen, Austen Grooms, Jessica Lasky-Su, Ida Surakka, Pradeep Natarajan, Michael Boehnke, Lukas Forer, Victor R. Gordeuk, Hyun Min Kang, Whitney E. Hornsby, Stella Aslibekyan, Wayne Huey-Herng Sheu, Ben Michael Brumpton, Sarah A Gagliano Taliun, Patrick T. Ellinor, Francesco Cucca, Karen Schwander, Patricia A. Peyser, Lewis C. Becker, Rebecca D. Jackson, Joanne E. Curran, Jonathon LeFaive, Sebastian Schoenherr, Marguerite R. Irvin, Sarah E. Graham, Eugene R. Bleecker, Solomon K. Musani, Michelle Daya, Alexander P. Reiner, Adolfo Correa, William Overton, Vivien A. Sheehan, Oddgeir L. Holmen, Cristen J. Willer, Bertha A. Hildalgo, Christian Fuchsberger, Chad M. Brummett, Sachin Kheterpal, Matthew Zawistowski, Kristian Hveem, Sekar Kathiresan, James G. Wilson, Marilyn J. Telen, Ramachandran S. Vasan, Bjørn Olav Åsvold, Donna K. Arnett, Sebastian Zöllner, Wei Zhou, Nicholette D. Palmer, Gonçalo R. Abecasis, Jennifer A. Smith, L. Adrienne Cupples, Nicholas M. Rafaels, Lawrence F. Bielak, Barbara A. Konkle, Charles Kooperberg, C Sidore, Juan M. Peralta, Jifeng Zhang, Daniel Taliun, Deborah A. Meyers, Stephen S. Rich, Sayantan Das, Jonas B. Nielsen, Thomas W. Blackwell, Oren Rom, Amanda Schaefer, Y. Eugene Chen, and Courtney G. Montgomery
Subjects: 2. Zero hunger, 0303 health sciences, education.field_of_study, business.industry, Population, Fatty liver, Blood lipids, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, Bioinformatics, medicine.disease, 3. Good health, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Diabetes mellitus, Medicine, Liver function, business, education, 030304 developmental biology
Abstract: SUMMARYCardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally.1Lowering circulating lipids is an important treatment strategy to reduce risk.2,3However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders.4,5,6To identify potential novel therapeutic targets, which may reduce risk of CVD without increasing risk of metabolic disease, we focused on the simultaneous evaluation of quantitative traits related to liver function and CVD. Using a combination of low-coverage (5×) whole-genome sequencing and targeted genotyping, deep genotype imputation based on the TOPMed reference panel7, and genome-wide association study (GWAS) meta-analysis, we analyzed 12 liver-related blood traits (including liver enzymes, blood lipids, and markers of iron metabolism) in up to 203,476 people from three population-based cohorts of different ancestries. We identified 88 likely causal protein-altering variants that were associated with one or more liver-related blood traits. We identified several loss-of-function (LoF) variants reducing low-density lipoprotein cholesterol (LDL-C) or risk of CVD without increased risk of liver disease or diabetes, including variants in known lipid genes (e.g.APOB,LPL). A novel LoF variant,ZNF529:p.K405X, was associated with decreased levels of LDL-C (P=1.3×10−8) but demonstrated no association with liver enzymes or non-fasting blood glucose levels. Silencing ofZNF529in human hepatocytes resulted in upregulation of LDL receptor (LDLR) and increased LDL-C uptake in the cells, suggesting that inhibition ofZNF529or its gene product could be used for treating hypercholesterolemia and hence reduce the risk of CVD. Taken together, we demonstrate that simultaneous consideration of multiple phenotypes and a focus on rare protein-altering variants may identify promising therapeutic targets.
Published: 2019
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109. Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

Author: Maiken Elvestad Gabrielsen, Matthew Zawistowski, Stein Hallan, Gonçalo R. Abecasis, Ida Surakka, Lars G. Fritsche, Matthew G. Sampson, Anne Heidi Skogholt, Wei Zhou, Sarah E. Graham, Damian Fermin, Hyun Min Kang, Whitney E. Hornsby, Chad M. Brummett, Sachin Kheterpal, Kristian Hveem, Seunggeun Lee, Solfrid Romundstad, Daniel B. Larach, Jonas B. Nielsen, and Cristen J. Willer
Subjects: 0301 basic medicine, Male, Quantitative trait loci, Science, General Physics and Astronomy, Renal function, Kidney development, Genome-wide association study, Genomics, Locus (genetics), 02 engineering and technology, Bioinformatics, Kidney, Genome-wide association studies, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, Article, Global Burden of Disease, 03 medical and health sciences, Sex Factors, Risk Factors, Chronic kidney disease, medicine, Humans, Renal Insufficiency, Chronic, lcsh:Science, Multidisciplinary, business.industry, urogenital system, General Chemistry, 021001 nanoscience & nanotechnology, medicine.disease, Prognosis, 3. Good health, 030104 developmental biology, Sample size determination, Genetic Loci, Meta-analysis, lcsh:Q, Female, 0210 nano-technology, business, Kidney disease, Genome-Wide Association Study, Glomerular Filtration Rate
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. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus 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 with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD., Estimated glomerular filtration rate (eGFR) is a measure of kidney function and used to characterize chronic kidney disease. Here, Graham et al. identify 53 novel loci for eGFR in a GWAS meta-analysis, a subset of which are associated with other common diseases, such as diabetes and hypertension, based on PheWAS.
Published: 2019

110. 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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111. Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts

Author: Wenjian Bi, Mark J. Daly, Jonas B. Nielsen, Kristian Hveem, Wei Zhou, Benjamin M. Neale, Gonçalo R. Abecasis, Lars G. Fritsche, Seunggeun Lee, Maiken Elvestad Gabrielsen, Jonathon LeFaive, Cristen J. Willer, and Sarah A Gagliano Taliun
Subjects: Mixed model, 0303 health sciences, education.field_of_study, Computer science, Aggregate (data warehouse), Population, Sample (statistics), Population stratification, Biobank, Generalized linear mixed model, 03 medical and health sciences, 0302 clinical medicine, Statistics, education, 030217 neurology & neurosurgery, 030304 developmental biology, Type I and type II errors
Abstract: With very large sample sizes, population-based cohorts and biobanks provide an exciting opportunity to identify genetic components of complex traits. To analyze rare variants, gene or region-based multiple variant aggregate tests are commonly used to increase association test power. However, due to the substantial computation cost, existing region-based rare variant tests cannot analyze hundreds of thousands of samples while accounting for confounders, such as population stratification and sample relatedness. Here we propose a scalable generalized mixed model region-based association test that can handle large sample sizes and accounts for unbalanced case-control ratios for binary traits. This method, SAIGE-GENE, utilizes state-of-the-art optimization strategies to reduce computational and memory cost, and hence is applicable to exome-wide and genome-wide region-based analysis for hundreds of thousands of samples. Through the analysis of the HUNT study of 69,716 Norwegian samples and the UK Biobank data of 408,910 White British samples, we show that SAIGE-GENE can efficiently analyze large sample data (N > 400,000) with type I error rates well controlled.
Published: 2019
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112. 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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113. 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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114. Variation in Serum PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9), Cardiovascular Disease Risk, and an Investigation of Potential Unanticipated Effects of PCSK9 Inhibition

Author: Humaira Rasheed, Lars E. Laugsand, Thor Ueland, Ida Surakka, George Davey Smith, Ferdinand M. van't Hooft, Pål Aukrust, Kristian Hveem, Sarah E. Graham, Jie Zheng, Bjørn Olav Åsvold, Jan Kristian Damås, Cristen J. Willer, Ben Michael Brumpton, Lars G. Fritsche, Maiken Elvestad Gabrielsen, Gunnhild Åberge Vie, Maria Nastase Mannila, John-Anker Zwart, Jonas B. Nielsen, Lars J. Vatten, Imre Janszky, and Nabil Georges Seidah
Subjects: 0303 health sciences, medicine.medical_specialty, Extramural, business.industry, Cholesterol, PCSK9, Subtilisin, General Medicine, 030204 cardiovascular system & hematology, Proprotein convertase, Hospital records, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, chemistry, Internal medicine, Disease risk, Medicine, Kexin, business, 030304 developmental biology
Published: 2019
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115. Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes

Author: Martin K. Rutter, Jaakko Kaprio, Ben Michael Brumpton, David A. Bechtold, Brian E. Cade, Tamar Sofer, Katri Kantojärvi, Sonja Sulkava, Frank A.J.L. Scheer, Cristen J. Willer, Samuel E. Jones, Bendik S. Winsvold, Shaun Purcell, Linn B Strand, Kai Spiegelhalder, Andrew R. Wood, David W. Ray, Richa Saxena, Jacqueline M. Lane, Andrew S. I. Loudon, Vincent T. van Hees, Yanwei Song, Jonas B. Nielsen, John-Anker Zwart, Kristian Hveem, Krunal Patel, Timothy M. Frayling, Hassan S. Dashti, Debbie A Lawlor, Kati Kristiansson, Teemu Palviainen, Simon G. Anderson, Richard Emsley, Heming Wang, Hanna Ollila, Christer Hublin, Simon D. Kyle, Susan Redline, Jessica Tyrrell, Michael N. Weedon, Jack Bowden, Rebecca C Richmond, Max A. Little, Tiina Paunio, Xiaofeng Zhu, Institute for Molecular Medicine Finland, University of Helsinki, Department of Medical and Clinical Genetics, Technology Centre, Genetic Epidemiology, Department of Public Health, Centre of Excellence in Complex Disease Genetics, Doctoral Programme Brain & Mind, Doctoral Programme in Clinical Research, Doctoral Programme in Population Health, Jaakko Kaprio / Principal Investigator, Quantitative Genetics, Doctoral Programme in Biomedicine, Clinicum, Department of Psychiatry, Doctoral Programme in Integrative Life Science, and HUS Psychiatry
Subjects: 0301 basic medicine, Male, Sleepiness, General Physics and Astronomy, RESTLESS LEGS, Excessive daytime sleepiness, Datasets as Topic, Genome-wide association study, 02 engineering and technology, Polysomnography, Genome-wide association studies, DISEASE, 0302 clinical medicine, APNEA, GENETIC INFLUENCES, Insomnia, 030212 general & internal medicine, Restless legs syndrome, DISTURBANCE, lcsh:Science, RISK, education.field_of_study, Multidisciplinary, medicine.diagnostic_test, HERITABILITY, 030503 health policy & services, Age Factors, General Medicine, Sleep disorders, IMPAIRMENT, Middle Aged, 021001 nanoscience & nanotechnology, Sleep in non-human animals, OBESITY, Female, medicine.symptom, 0210 nano-technology, 0305 other medical science, Clinical psychology, Adult, WAKEFULNESS, Science, Population, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Young Adult, Sex Factors, medicine, Humans, education, Aged, business.industry, 3112 Neurosciences, Chronotype, General Chemistry, medicine.disease, Obesity, 030104 developmental biology, Genetic Loci, lcsh:Q, Self Report, business, Sleep, Genome-Wide Association Study
Abstract: Excessive daytime sleepiness (EDS) affects 10–20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing., A main symptom of chronic insufficient sleep is excessive daytime sleepiness. Here, Wang et al. report 42 genome-wide significant loci for self-reported daytime sleepiness in 452,071 individuals from the UK Biobank that cluster into two biological subtypes of either sleep propensity or sleep fragmentation.
Published: 2019
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116. Receptor-Mediated ER Export of Lipoproteins Controls Lipid Homeostasis in Mice and Humans

Author: Xiaowei Chen, Cristen J. Willer, Dong Huang, Yuangang Zhu, Chao Nie, Gregory J.M. Zajac, Fangyuan Shi, Bolin Xu, Jianye Dai, Rui Wang, Longjun Pu, Yan Wang, Brian T. Emmer, Xiaohui Dong, Xiangfeng Lu, Ge Gao, Chu Wang, Huimin Wang, Han Yan, Jia Lu, Jingru Zhao, Wenjing Zhou, and Xiao Wang
Subjects: Male, 0301 basic medicine, Physiology, Lipoproteins, Mice, Transgenic, GTPase, Endoplasmic Reticulum, Mice, 03 medical and health sciences, 0302 clinical medicine, Animals, Homeostasis, Humans, Secretion, Receptor, Molecular Biology, COPII, Cells, Cultured, Secretory pathway, Monomeric GTP-Binding Proteins, Chemistry, Endoplasmic reticulum, Membrane Proteins, Translation (biology), Cell Biology, Receptor-mediated endocytosis, Lipids, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, 030217 neurology & neurosurgery
Abstract: Summary Efficient delivery of specific cargos in vivo poses a major challenge to the secretory pathway, which shuttles products encoded by ∼30% of the genome. Newly synthesized protein and lipid cargos embark on the secretory pathway via COPII-coated vesicles, assembled by the GTPase SAR1 on the endoplasmic reticulum (ER), but how lipid-carrying lipoproteins are distinguished from the general protein cargos in the ER and selectively secreted has not been clear. Here, we show that this process is quantitatively governed by the GTPase SAR1B and SURF4, a high-efficiency cargo receptor. While both genes are implicated in lipid regulation in humans, hepatic inactivation of either mouse Sar1b or Surf4 selectively depletes plasma lipids to near-zero and protects the mice from atherosclerosis. These findings show that the pairing between SURF4 and SAR1B synergistically operates a specialized, dosage-sensitive transport program for circulating lipids, while further suggesting a potential translation to treat atherosclerosis and related cardio-metabolic diseases.
Published: 2021
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117. 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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118. Genetic Variants in LRP1 and ULK4 Are Associated with Acute Aortic Dissections

Author: Bo Yang, Scott A. LeMaire, Anthony L. Estrera, Hazim J. Safi, Simon C. Body, Dianna M. Milewicz, Siddharth K. Prakash, Ellen M. Hostetler, Sherene Shalhub, Dongchuan Guo, Kim A. Eagle, Per Eriksson, Cristen J. Willer, Ellen S. Regalado, Eric Boerwinkle, Megan L. Grove, Michael R. Mathis, and Wei Zhou
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Linkage disequilibrium, DNA Copy Number Variations, Genotype, Fibrillin-1, Single-nucleotide polymorphism, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Sudden death, Linkage Disequilibrium, Cohort Studies, 03 medical and health sciences, Aortic aneurysm, Aneurysm, Risk Factors, Report, Internal medicine, Genetics, medicine, Humans, Genetics(clinical), Exome, Genetic Predisposition to Disease, Genetic Association Studies, Genetics (clinical), Aged, Genetic association, Aortic dissection, Aortic Aneurysm, Thoracic, business.industry, Case-control study, Genetic Variation, Middle Aged, Atherosclerosis, medicine.disease, Europe, Aortic Dissection, 030104 developmental biology, Case-Control Studies, Hypertension, Female, business, Gene Deletion, Low Density Lipoprotein Receptor-Related Protein-1
Abstract: Acute aortic dissections are a preventable cause of sudden death if individuals at risk are identified and surgically repaired in a non-emergency setting. Although mutations in single genes can be used to identify at-risk individuals, the majority of dissection case subjects do not have evidence of a single gene disorder, but rather have the other major risk factor for dissections, hypertension. Initial genome-wide association studies (GWASs) identified SNPs at the FBN1 locus associated with both thoracic aortic aneurysms and dissections. Here, we used the Illumina HumanExome array to genotype 753 individuals of European descent presenting specifically with non-familial, sporadic thoracic aortic dissection (STAD) and compared them to the genotypes of 2,259 control subjects from the Atherosclerosis Risk in Communities (ARIC) study matched for age, gender, and, for the majority of cases, hypertension. SNPs in FBN1, LRP1, and ULK4 were identified to be significantly associated with STAD, and these results were replicated in two independent cohorts. Combining the data from all cohorts confirmed an inverse association between LRP1 rs11172113 and STAD (p = 2.74 × 10(-8); OR = 0.82, 95% CI = 0.76-0.89) and a direct association between ULK4 rs2272007 and STAD (p = 1.15 × 10(-9); OR = 1.35, 95% CI = 1.23-1.49). Genomic copy-number variation analysis independently confirmed that ULK4 deletions were significantly associated with development of thoracic aortic disease. These results indicate that genetic variations in LRP1 and ULK4 contribute to risk for presenting with an acute aortic dissection.
Published: 2016
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119. 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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120. 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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121. 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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122. The Emerging Landscape of Epidemiological Research Based on Biobanks Linked to Electronic Health Records: Existing Resources, Analytic Challenges and Potential Opportunities

Author: Cristen J. Willer, Bhramar Mukherjee, Anita Pandit, Rao A, Lauren J. Beesley, Maxwell Salvatore, Lars G. Fritsche, Chad M. Brummett, and Lynda D. Lisabeth
Subjects: 0303 health sciences, medicine.medical_specialty, Health records, Biobank, Data science, 03 medical and health sciences, general_medical_research, 0302 clinical medicine, Geography, Epidemiology, Research based, medicine, 030212 general & internal medicine, 030304 developmental biology
Abstract: Biobanks linked to electronic health records provide a rich data resource for health-related research. With the establishment of large-scale infrastructure, the availability and utility of data from biobanks has dramatically increased over time. As more researchers become interested in using biobank data to explore a diverse spectrum of scientific questions, resources guiding the data access, design, and analysis of biobank-based studies will be crucial. The first aim of this review is to characterize the types of biobanks that are discussed in the recent literature and provide detailed descriptions of specific biobanks including their location, size, data access, data linkages and more. The development and accessibility of large-scale biorepositories provide the opportunity to accelerate agnostic searches, new discoveries, and hypothesis-generating studies of disease-treatment, disease-exposure and disease-gene associations. Rather than spending time and money designing and implementing a single study with pre-defined objectives, researchers can use biobanks’ existing data-rich resources to answer scientific questions as quickly as they can analyze them. While the data are becoming increasingly available, additional thought is needed to address issues related to the design of such studies and analysis of these data. In the second aim of this review, we discuss statistical issues related to biobank research in general including study design, sampling strategy, phenotype identification, and missing data. These issues are illustrated using data from the Michigan Genomics Initiative, UK Biobank, and Genes for Good. We summarize the current body of statistical literature aimed at addressing some of these challenges and discuss some of the standing open problems in this area. This work serves to complement and extend recent reviews about biobank-based research and aims to provide a resource catalog with statistical and practical guidance to researchers pursuing biobank-based research.
Published: 2018

123. 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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124. Robust meta-analysis of biobank-based genome-wide association studies with unbalanced binary phenotypes

Author: Wei Zhou, J. B. Nielsen, Huanhuan Zhu, Seunggeun Lee, Rounak Dey, Lars G. Fritsche, and Cristen J. Willer
Subjects: Score test, Genotype, Epidemiology, Computer science, Association (object-oriented programming), Genome-wide association study, computer.software_genre, Article, 03 medical and health sciences, Humans, Computer Simulation, Genetics (clinical), Statistic, 030304 developmental biology, Genetic association, Biological Specimen Banks, 0303 health sciences, Models, Genetic, 030305 genetics & heredity, Numerical Analysis, Computer-Assisted, Biobank, United Kingdom, Meta-analysis, Data mining, computer, Type I and type II errors, Genome-Wide Association Study
Abstract: With the availability of large-scale biobanks, genome-wide scale phenome-wide association studies are being instrumental in discovering novel genetic variants associated with clinical phenotypes. As increasing number of such association results from different biobanks become available, methods to meta-analyse those association results is of great interest. Because the binary phenotypes in biobank-based studies are mostly unbalanced in their case-control ratios, very few methods can provide well-calibrated tests for associations. For example, traditional Z score-based meta-analysis often results in conservative or anti-conservative type I error rates in such unbalanced scenarios. We propose two meta-analysis strategies that can efficiently combine association results from biobank-based studies with such unbalanced phenotypes, using the saddlepoint approximation-based score test method (SPA). Our first method involves sharing the overall genotype counts from each study, and the second method involves sharing an approximation of the distribution of the score test statistic from each study using cubic Hermite splines. We compare our proposed methods with a traditional Z score-based meta-analysis strategy using numerical simulations and real data applications, and demonstrate the superior performance of our proposed methods in terms of type I error control.
Published: 2018

125. 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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126. 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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127. Coding variants in

Author: Rosa B, Thorolfsdottir, Gardar, Sveinbjornsson, Patrick, Sulem, Jonas B, Nielsen, Stefan, Jonsson, Gisli H, Halldorsson, Pall, Melsted, Erna V, Ivarsdottir, Olafur B, Davidsson, Ragnar P, Kristjansson, Gudmar, Thorleifsson, Anna, Helgadottir, Solveig, Gretarsdottir, Gudmundur, Norddahl, Sridharan, Rajamani, Bjarni, Torfason, Atli S, Valgardsson, Jon T, Sverrisson, Vinicius, Tragante, Oddgeir L, Holmen, Folkert W, Asselbergs, Dan M, Roden, Dawood, Darbar, Terje R, Pedersen, Marc S, Sabatine, Cristen J, Willer, Maja-Lisa, Løchen, Bjarni V, Halldorsson, Ingileif, Jonsdottir, Kristian, Hveem, David O, Arnar, Unnur, Thorsteinsdottir, Daniel F, Gudbjartsson, Hilma, Holm, and Kari, Stefansson
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
Published: 2018

128. Biological and clinical insights from genetics of insomnia symptoms

Author: Hassan S. Dashti, Frank A.J.L. Scheer, Andrew R. Wood, Robin N Beaumont, Yanwei Song, Brian E. Cade, Kristian Hveem, Richa Saxena, Martin K. Rutter, Debbie A Lawlor, Max A. Little, Ben Michael Brumpton, Simon D. Kyle, Jack Bowden, Sekar Kathiresan, Rebecca C Richmond, Jacqueline M. Lane, Simon G. Anderson, Vincent T. van Hees, Hunt All In Sleep, Jessica Tyrrell, Linn B Strand, Cristen J. Willer, John W. Winkelman, Andrew S. I. Loudon, Samuel E. Jones, Kai Spiegelhalder, Krunal Patel, Timothy M. Frayling, Susan Redline, Heming Wang, David W. Ray, Annemarie I. Luik, Krishna G. Aragam, Shaun Purcell, Bendik S. Winsvold, Jonas B. Nielsen, David A. Bechtold, John-Anker Zwart, and Michael N. Weedon
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Disease, medicine.disease, Sleep in non-human animals, Biobank, Coronary heart disease, Pathophysiology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, mental disorders, Insomnia, medicine, Causal link, Restless legs syndrome, medicine.symptom, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying pathophysiological processes and causal relationships 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, phototransduction and muscle development pathways 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 heart disease, depressive symptoms and subjective well-being.One Sentence SummaryWe identify 57 genomic regions associated with insomnia pointing to the involvement of phototransduction and ubiquitination and potential causal links to CAD and depression.
Published: 2018
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129. 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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130. 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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131. 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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132. 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

133. Abstract 154: Genetic Variants in CETP That Increase HDL Levels also Increase Risk of Intracerebral Hemorrhage

Author: Gina M. Peloso, Catherine Sudlow, Chelsea S. Kidwell, Christopher D. Anderson, Gonçalo R. Abecasis, Farid Radmanesh, Devin L. Brown, Arne Lindgren, Magdy Selim, Steven J. Kittner, Bo Norrving, Kristiina Rannikmäe, David L. Tirschwell, Jordi Jimenez-Conde, James F. Meschia, Agnieszka Slowik, Alessandro Pezzini, Joan Montaner, Carl D. Langefeld, Bradford B. Worrall, Daniel Woo, Guido J. Falcone, Chia-Ling Phuah, Cristen J. Willer, Jonathan Rosand, Sekar Kathiresan, Scott Silliman, and Catharina J.M. Klijn
Subjects: Advanced and Specialized Nursing, Intracerebral hemorrhage, medicine.medical_specialty, business.industry, Genetic variants, medicine.disease, Endocrinology, Increased risk, Internal medicine, medicine, lipids (amino acids, peptides, and proteins), Neurology (clinical), Spontaneous intracerebral hemorrhage, Cardiology and Cardiovascular Medicine, business, Lipoprotein cholesterol
Abstract: Introduction: In observational studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of spontaneous intracerebral hemorrhage (ICH). Common DNA sequence variants within the cholesteryl ester transfer protein ( CETP ) gene decrease CETP protein activity and increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development to combat coronary artery disease. Hypothesis: Common CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed a two-stage case-control genetic association study in Caucasians. The discovery phase utilized data on 12 independent loci within CETP (+/- 50 kilobases) from 3 genome-wide association studies of ICH. Replication involved direct genotyping in 5 additional studies. We also constructed a genetic risk score with 7 independent CETP variants and tested it for association with HDL-C and ICH risk. We used principal component analysis to account for population structure and a Bonferroni-adjusted p Results: The discovery phase included 1149 ICH cases (43% lobar hemorrhages) and 1238 controls. Twelve variants were nominally associated (p-4 ) and no heterogeneity across studies (I 2 =0%). This association was replicated in 1625 cases (43% lobar hemorrhages) and 1845 controls (OR 1.12, 95%CI 1.02-1.24; p=0.03). A genetic score of independent CETP variants known to increase HDL-C by ~2.85 mg/dL was strongly associated with ICH risk (OR 1.86, 95%CI 1.44-2.40; p=1.4x10 -6 ). Conclusion: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes is warranted.
Published: 2017
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134. 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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135. 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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136. 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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137. POLYPHARMACY AND POTENTIALLY INAPPROPRIATE MEDICATION USE ARE UNIVERSAL AMONG PATIENTS WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION

Author: Jennifer McNamara, Whitney E. Hornsby, Michael Brenner, Cristen J. Willer, Matthew C. Konerman, Lina M. Brinker, Scott L. Hummel, Michael P. Dorsch, and Parag Goyal
Subjects: Polypharmacy, medicine.medical_specialty, Medication use, business.industry, medicine, Cardiology and Cardiovascular Medicine, Intensive care medicine, business, Heart failure with preserved ejection fraction
Abstract: Heart failure with preserved ejection fraction (HFpEF) lacks specific evidence-based therapy, but patients still often take many medications for HFpEF and concurrent comorbid conditions. We aimed to describe medication burden and patterns of potentially harmful medication use in HFpEF. We performed
Published: 2019
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138. 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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139. 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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140. 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

141. 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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142. Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance

Author: Neil Risch, Cristen J. Willer, Matthew R. Lincoln, M. Zameel Cader, David A. Dyment, Blanca M. Herrera, George C. Ebers, and A. Dessa Sadovnick
Subjects: musculoskeletal diseases, Multiple Sclerosis, Offspring, Locus (genetics), Human leukocyte antigen, Major histocompatibility complex, Major Histocompatibility Complex, immune system diseases, Genotype, Genetics, Humans, Genetic Predisposition to Disease, Allele, skin and connective tissue diseases, Molecular Biology, Genotyping, Genetics (clinical), Alleles, biology, Haplotype, General Medicine, HLA-DR Antigens, Haplotypes, Immunology, biology.protein, HLA-DRB1 Chains
Abstract: Mechanisms for observed associations within the major histocompatibility complex (MHC) and autoimmune diseases including multiple sclerosis (MS) remain uncertain. Genotyping of the HLA Class II DRB1 locus in 4347 individuals from 873 multiplex families with MS highlights the genetic complexity of this locus. Excess allele sharing in sibling pair families lacking DRB1*15 and DRB1*17 (58.5% sharing; P=0.012) was comparable to that seen where parents were DRB1*15 positive (62%, P=0.0006). DRB1*17 (P=0.00027) was clearly established as an MS susceptibility allele in addition to DRB1*15 (P
Published: 2016

143. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Author: Bo Isomaa, Anne U. Jackson, Richard N. Bergman, A Sandbaek, Yun Li, Oluf Pedersen, Thomas Edward Hughes, Mike Erdos, Christine Meisinger, Kari Kubalanza, Felicity Payne, Mark Walker, E Pettersen, William L. Duren, Kristin Ardlie, Palmer Cna., Michael Boehnke, Peter M. Nilsson, Graham A. Hitman, Rachel M. Freathy, Matthew G. Rees, Johanna Kuusisto, Finny G Kuruvilla, Kari Stefansson, P Deodhar, Knut Borch-Johnsen, Perry Jrb., Inês Barroso, Hana Lango, Richa Saxena, Augustine Kong, Gonçalo R. Abecasis, Katherine S. Elliott, Jonathan Marchini, Richard M. Watanabe, Christopher J. Groves, Niels Grarup, Unnur Thorsteinsdottir, Doney Asf., Kristina Bengtsson Boström, Peter Almgren, Cristen J. Willer, Torben Jørgensen, Lauren Gianniny, Beverley M. Shields, Christian Herder, Mario A. Morken, Lu Qi, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Nigel W. Rayner, Benjamin F. Voight, H Chen, J J Roix, Karen L. Mohlke, Heather M. Stringham, Andrew D. Morris, Mark I. McCarthy, Gudmar Thorleifsson, Frank B. Hu, Narisu Narisu, Mark J. Daly, Amanda F. Marvelle, Markku Laakso, Leif Groop, Laura J. Scott, Ding C-J., L Qin, Lori L. Bonnycastle, Thomas Illig, Noël P. Burtt, Michael N. Weedon, Valeriya Lyssenko, Amy J. Swift, Timothy M. Frayling, Nicholas J. Wareham, de Bakker Piw., Tiinamaija Tuomi, Kristian Hveem, Candace Guiducci, T Hu, Andrew T. Hattersley, David Altshuler, Harald Grallert, Peter S. Chines, Inga Prokopenko, Torsten Lauritzen, Katharine R. Owen, Eleftheria Zeggini, Carl Platou, Marketa Sjögren, Jaakko Tuomilehto, Nicholas J. Timpson, Francis S. Collins, Kristian Midthjell, Gregers S. Andersen, Claudia Langenberg, and Torben Hansen
Subjects: Genetics, 0303 health sciences, endocrine system, SLC30A8, Genome, Human, 030209 endocrinology & metabolism, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Heritability, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Diabetes Mellitus, Type 2, Meta-analysis, biology.protein, Humans, Genetic Predisposition to Disease, Human genome, CDKAL1, 030304 developmental biology
Abstract: Udgivelsesdato: 2008-May Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
Published: 2016
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144. Common variants at 30 loci contribute to polygenic dyslipidemia

Author: Michael Boehnke, Luigi Ferrucci, Aarti Surti, Jaakko Tuomilehto, Karen L. Mohlke, Candace Guiducci, Lee M. Kaplan, Rory Collins, Leena Peltonen, Qiong Yang, Cristen J. Willer, Francis S. Collins, Angelo Scuteri, Christopher J. O'Donnell, Edward G. Lakatta, Serkalem Demissie, Johanna Kuusisto, John C. Chambers, Amy J. Swift, Leif Groop, Markku Laakso, Gina M. Peloso, Sekar Kathiresan, Jouko Sundvall, G. Mark Lathrop, Gonçalo R. Abecasis, Benjamin F. Voight, Jose M. Ordovas, Veikko Salomaa, Eric E. Schadt, Robert Clarke, David Altshuler, David Schlessinger, Diana Zelenika, Pilar Galan, Serge Hercberg, Derrick A Bennett, Kari Kubalanza, Laura J. Scott, Kiran Musunuru, Kathryn L. Lunetta, Serena Sanna, Marju Orho-Melander, L. Adrienne Cupples, Toshiko Tanaka, Gabriel Crawford, Pierre Meneton, Josée Dupuis, Anne U. Jackson, Sarah Parish, Paul I.W. de Bakker, Yun Li, Olle Melander, Mario A. Morken, Manuela Uda, Heather M. Stringham, Lori L. Bonnycastle, Noël P. Burtt, Paul Scheet, Richard N. Bergman, and Jaspal S. Kooner
Subjects: Adult, Male, Multifactorial Inheritance, medicine.medical_specialty, Quantitative Trait Loci, Blood lipids, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, chemistry.chemical_compound, Delta-5 Fatty Acid Desaturase, 0302 clinical medicine, Meta-Analysis as Topic, ANGPTL4, Internal medicine, Genetics, medicine, Humans, RNA, Messenger, Allele, Alleles, Triglycerides, Dyslipidemias, 030304 developmental biology, 0303 health sciences, Triglyceride, Cholesterol, Cholesterol, HDL, Reproducibility of Results, Cholesterol, LDL, Syndrome, Middle Aged, medicine.disease, 3. Good health, Phenotype, Endocrinology, Gene Expression Regulation, Liver, chemistry, Female, lipids (amino acids, peptides, and proteins), Dyslipidemia, Genome-Wide Association Study, Lipoprotein
Abstract: Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
Published: 2016

145. Hepatic Transmembrane 6 Superfamily Member 2 Regulates Cholesterol Metabolism in Mice

Author: Cristen J. Willer, Zhisheng Jiang, Minerva Garcia-Barrio, Tianqing Zhu, Yanbo Fan, Y. Eugene Chen, Yanhong Guo, Jifeng Zhang, and Haocheng Lu
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Time Factors, Genotype, Transgene, Cholesterol 7 alpha-hydroxylase, Diet, High-Fat, Transfection, Article, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Internal medicine, medicine, Animals, Humans, Liver X receptor, Triglycerides, Mice, Knockout, Hepatology, biology, Triglyceride, Cholesterol, HDL, Gastroenterology, Membrane Proteins, Metabolism, Cholesterol, LDL, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Cholesterol, Phenotype, chemistry, Gene Expression Regulation, Liver, ABCG5, biology.protein, lipids (amino acids, peptides, and proteins), 030211 gastroenterology & hepatology, Female, Biomarkers, TM6SF2
Abstract: Background & Aims The rs58542926 C>T variant of the transmembrane 6 superfamily member 2 gene (TM6SF2), encoding an E167K amino acid substitution, has been correlated with reduced total cholesterol (TC) and cardiovascular disease. However, little is known about the role of TM6SF2 in metabolism. We investigated the long-term effects of altered TM6SF2 levels in cholesterol metabolism. Methods C57BL/6 mice (controls), mice that expressed TM6SF2 specifically in the liver, and mice with CRISPR/Cas9-mediated knockout of Tm6sf2 were fed chow or high-fat diets. Blood samples were collected from all mice and plasma levels of TC, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol, and triglycerides were measured. Liver tissues were collected and analyzed by histology, real-time polymerase chain reaction, and immunoblot assays. Adenovirus vectors were used to express transgenes in cultured Hep3B hepatocytes. Results Liver-specific expression of TM6SF2 increased plasma levels of TC and LDL-c, compared with controls, and altered liver expression of genes that regulate cholesterol metabolism. Tm6sf2-knockout mice had decreased plasma levels of TC and LDL-c, compared with controls, and consistent changes in expression of genes that regulate cholesterol metabolism. Expression of TM6SF2 promoted cholesterol biosynthesis in hepatocytes. Conclusions TM6SF2 regulates cholesterol metabolism in mice and might be a therapeutic target for cardiovascular disease.
Published: 2016

146. Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Author: Adnan Kastrati, Wu Yin, Jeanette Erdmann, Ruth J. F. Loos, Paul L. Auer, Susanne Moebus, Christina Willenborg, Piera Angelica Merlini, Jochen Kruppa, Anubha Mahajan, Julian C. van Capelleveen, Christa Meisinger, Charles Kooperberg, Natalie R. van Zuydam, Domenico Girelli, Erik P A Van Iperen, Rebecca D. Jackson, Tom R. Webb, Dan M. Roden, Ursula M. Schick, Colin N. A. Palmer, Eli A. Stahl, Mark I. McCarthy, Andres Metspalu, David-Alexandre Trégouët, Markus Perola, Kathleen Stirrups, G. Kees Hovingh, Martina Mueller-Nurasyid, Maris Alver, Christopher Newton-Cheh, Daniel J. Rader, Karl-Heinz Joeckel, Karen O. Akinsanya, Nilesh J. Samani, Alistair S. Hall, Stefano Duga, Louise A. Donnelly, J. Wouter Jukema, Nour Eddine El-Mokhtari, Rosanna Asselta, Tibor V. Varga, Heribert Schunkert, Erwin P. Bottinger, Paola G. Ferrario, Nathan O. Stitziel, Nicola Marziliano, Marie-Pierre Dubé, Andre Franke, Robert A. Scott, Thomas Meitinger, Stavroula Kanoni, Jan-Håkan Jansson, Christian Hengstenberg, Svati H. Shah, Josh C. Denny, Melanie Waldenberger, Alex S. F. Doney, Nicola Martinelli, Cristen J. Willer, Olle Melander, Hugh Watkins, He Zhang, Inke R. Koenig, Ron Do, Thomas F. Vogt, Chunyu Liu, Omri Gottesman, Kari Kuulasmaa, Peter S. Braund, Praveen Surendran, Dermot F. Reilly, Per Hoffmann, Georg Ehret, Karl L. Laugwitz, Diego Ardissino, Børge G. Nordestgaard, Joanna M. M. Howson, Raimund Erbel, Stefan A. Escher, Wolfgang Lieb, Hong-Hee Won, Majid Nikpay, Martin Farrall, Stefanie Heilmann, Ruth McPherson, Nicholas G. D. Masca, Evelin Mihailov, Danish Saleheen, Andrew D. Morris, Neil R. Robertson, Oddgeir L. Holmen, Sekar Kathiresan, Annette Peters, Jean-Claude Tardif, Alaa AlQarawi, Frank Kee, Jennifer Kriebel, Panos Deloukas, Anuj Goel, Kristian Hveem, Konstantin Strauch, Alexander P. Reiner, Paul W. Franks, John R. Thompson, Robin Young, William E. Kraus, Nicholas J. Wareham, Aldi T. Kraja, Rajiv Chowdhury, Oliviero Olivieri, Folkert W. Asselbergs, Adam S. Butterworth, Daniel I. Chasman, Gina M. Peloso, Peter Weeke, Christian M. Shaffer, Naveed Sattar, Muredach P. Reilly, John Danesh, Marco M Ferrario, Ian Ford, Lingyao Zeng, Marju Orho-Melander, Louis-Philippe Lemieux Perreault, Tõnu Esko, Eirini Marouli, Thorsten Kessler, Yingchang Lu, Ehret, Georg Benedikt, Vascular Medicine, Graduate School, and ACS - Amsterdam Cardiovascular Sciences
Subjects: 0301 basic medicine, Male, Pathology, Heart disease, Genotyping Techniques, Aged, Angiopoietins, Cell Adhesion Molecules, Coronary Artery Disease, Female, Humans, Lipoprotein Lipase, Middle Aged, Mutation, Missense, Risk Factors, Sequence Analysis, DNA, Triglycerides, Mutation, Medicine (all), Medizin, 030204 cardiovascular system & hematology, Coronary disease, Bioinformatics, medicine.disease_cause, Coronary artery disease, 0302 clinical medicine, ANGPTL4, Angiopoietin-like 4 Protein, Non-U.S. Gov't, ddc:616, Research Support, Non-U.S. Gov't, Coronary Artery Disease/genetics, General Medicine, 3. Good health, Variation (linguistics), Cardiology, Medical genetics, LPL, Cell Adhesion Molecules/genetics, Sequence Analysis, ANGPTL4, LPL, SVEP1 and coronary artery disease, medicine.medical_specialty, Lipoprotein Lipase/antagonists & inhibitors/genetics/metabolism, Research Support, Article, SVEP1 and coronary artery disease, N.I.H, 03 medical and health sciences, Triglycerides/blood/genetics, Research Support, N.I.H., Extramural, Internal medicine, Angiopoietins/genetics, Journal Article, medicine, Genotyping, business.industry, PCSK9, Extramural, DNA, medicine.disease, 030104 developmental biology, Missense, business, Coding (social sciences)
Abstract: BACKGROUND: \ud \ud The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets.\ud \ud METHODS: \ud \ud Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes.\ud \ud RESULTS: \ud \ud We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)).\ud \ud CONCLUSIONS: \ud \ud We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).
Published: 2016

147. Genetic variants in CETP increase risk of intracerebral hemorrhage

Author: Christopher D, Anderson, Guido J, Falcone, Chia-Ling, Phuah, Farid, Radmanesh, H Bart, Brouwers, Thomas W K, Battey, Alessandro, Biffi, Gina M, Peloso, Dajiang J, Liu, Alison M, Ayres, Joshua N, Goldstein, Anand, Viswanathan, Steven M, Greenberg, Magdy, Selim, James F, Meschia, Devin L, Brown, Bradford B, Worrall, Scott L, Silliman, David L, Tirschwell, Matthew L, Flaherty, Peter, Kraft, Jeremiasz M, Jagiella, Helena, Schmidt, Björn M, Hansen, Jordi, Jimenez-Conde, Eva, Giralt-Steinhauer, Roberto, Elosua, Elisa, Cuadrado-Godia, Carolina, Soriano, Koen M, van Nieuwenhuizen, Catharina J M, Klijn, Kristiina, Rannikmae, Neshika, Samarasekera, Rustam, Al-Shahi Salman, Catherine L, Sudlow, Ian J, Deary, Andrea, Morotti, Alessandro, Pezzini, Joanna, Pera, Andrzej, Urbanik, Alexander, Pichler, Christian, Enzinger, Bo, Norrving, Joan, Montaner, Israel, Fernandez-Cadenas, Pilar, Delgado, Jaume, Roquer, Arne, Lindgren, Agnieszka, Slowik, Reinhold, Schmidt, Chelsea S, Kidwell, Steven J, Kittner, Salina P, Waddy, Carl D, Langefeld, Goncalo, Abecasis, Cristen J, Willer, Sekar, Kathiresan, Daniel, Woo, and Jonathan, Rosand
Subjects: Adult, Male, Genotype, Cholesterol, HDL, Clinical Neurology, Middle Aged, Neurology, Neurology (clinical), Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Polymorphism, Single Nucleotide, Cholesterol Ester Transfer Proteins, carbohydrates (lipids), Research Support, N.I.H., Extramural, Journal Article, Humans, Female, Genetic Predisposition to Disease, lipids (amino acids, peptides, and proteins), Research Articles, Aged, Cerebral Hemorrhage, Research Article
Abstract: Contains fulltext : 167830.pdf (Publisher’s version ) (Open Access) OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 x 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by approximately 2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 x 10-6 ). INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.
Published: 2016

148. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author: Timo A. Lakka, Kathleen Stirrups, Jean Ferrières, Ying Wu, Gulum Kosova, Toby Johnson, Heather M. Stringham, Bruce M. Psaty, Bruna Gigante, Göran Hallmans, Cornelia M. van Duijn, Kae Woei Liang, Niclas Eriksson, N. William Rayner, Lynda M. Rose, Stavroula Kanoni, Xueling Sim, Evangelos Evangelou, Philippe Froguel, Michel Burnier, Andrew P. Morris, Olle Melander, Martin Farrall, Albert V. Smith, Brendan J. Keating, Thomas Illig, Johan Sundström, Dorret I. Boomsma, Kate Witkowska, Ellen M. Schmidt, Aki S. Havulinna, Ann-Kristin Petersen, Paul F. O'Reilly, Young Jin Kim, Kari Kuulasmaa, Tom Wilsgaard, John D. Eicher, Marcus E. Kleber, Francis S. Collins, Rona J. Strawbridge, Ronald M. Krauss, Fotios Drenos, Stuart K. Kim, Ken K. Ong, Pascal Bovet, Danish Saleheen, Jaspal S. Kooner, Karl-Heinz Herzig, Tien Yin Wong, Benjamin F. Voight, Stefania Bandinelli, Stéphane Lobbens, Colin A. McKenzie, Jing Hua Zhao, Terrence Forrester, Louise A. Donnelly, Alice Stanton, Jean Dallongeville, Kirill V. Tarasov, Narisu Narisu, Jürgen Gräßler, Luigi Ferrucci, Peter S. Sever, Paul Elliott, Tune H. Pers, Andrew J. Smith, Tomas Axelsson, Young Ah Shin, Nora Franceschini, James F. Wilson, Vilmundur Gudnason, Kati Kristiansson, Andrew A. Hicks, Kent D. Taylor, Genovefa Kolovou, Andrew D. Morris, André G. Uitterlinden, Serena Sanna, Xiuqing Guo, Honghuang Lin, Aravinda Chakravarti, Wayne Huey-Herng Sheu, Panos Deloukas, Linda S. Adair, Diana Kuh, Murielle Bochud, Eric Boerwinkle, Inger Njølstad, Meena Kumari, Norman Klopp, Leo-Pekka Lyytikäinen, Steven C. Hunt, Weihua Zhang, Tõnu Esko, Pierre Meneton, Markus Perola, Erik P A Van Iperen, Georg Ehret, Veikko Salomaa, Lars Lind, Zoltán Kutalik, Cristiano Fava, Caroline Hayward, Hugh S. Markus, Teresa Ferreira, Stefan R. Bornstein, Vasyl Pihur, Patricia B. Munroe, Anne U. Jackson, Eirini Marouli, Gabriele Müller, Damiano Baldassarre, Jacques E. Rossouw, Dan E. Arking, Maija Hassinen, Nicholas J. Wareham, Robert Roberts, Daniel I. Chasman, I. Shou Chang, Sylvain Sebert, Tove Fall, Roby Joehanes, Patrik K. E. Magnusson, John C. Chambers, Peter Vollenweider, Wen Jane Lee, Dmitry Shungin, Mathias Gorski, Christopher Newton-Cheh, Anders Franco-Cereceda, Ching-Yu Cheng, Yun Kyoung Kim, Ruth J. F. Loos, Lude Franke, Karen L. Mohlke, Yii-Der Ida Chen, Carlos Iribarren, Martina Müller-Nurasyid, Alexander Teumer, Andrew D. Johnson, Antonella Mulas, Ulf Gyllensten, Martin D. Tobin, George Dedoussis, Rainford J. Wilks, Joshua C. Bis, Beverley Balkau, Jie Yao, Frida Renström, Themistocles L. Assimes, Morris Brown, Inês Barroso, Hyun Min Kang, Loic Yengo, Mika Kähönen, Christopher J. Groves, Kirsti Kvaløy, Rainer Rauramaa, Heribert Schunkert, Satu Männistö, Marjo-Riitta Järvelin, Nancy L. Pedersen, Karl Gertow, Rick Jansen, Thomas Quertermous, Jarmo Virtamo, Lazaros Lataniotis, Serge Hercberg, Paul M. Ridker, Osorio Meirelles, Jostein Holmen, Phil Howard, G. Kees Hovingh, Jeanette Erdmann, Jong-Young Lee, Peter Schwarz, Ramaiah Nagaraja, Elizabeth Theusch, Wei Zhao, Sonia Shah, Chao A. Hsiung, Santhi K. Ganesh, Richard S. Cooper, John M. C. Connell, Jian'an Luan, Graciela E. Delgado, Eric Kim, Daniel Levy, Li Lin, Jerome I. Rotter, Andres Metspalu, Nabila Bouatia-Naji, Christopher J. O'Donnell, Roberto Elosua, Andrew Wong, Alanna C. Morrison, Juha Saltevo, Michael R. Barnes, Alan B. Weder, Kay-Tee Khaw, Leena Moilanen, Peter S. Chines, Claudia Langenberg, Marika Kaakinen, Asif Rasheed, Annette Peters, Angela Döring, Alena Stančáková, Richard A. Jensen, Jaana Lindström, Alison H. Goodall, Toshiko Tanaka, Loukianos S. Rallidis, Dabeeru C. Rao, Ann-Christine Syvänen, Alun Evans, Brenda W.J.H. Penninx, Sarah Edkins, Xiaohui Li, Neil Poulter, Jouko Saramies, Ulf de Faire, Walter Palmas, Jaakko Tuomilehto, Louise V. Wain, Cristina Menni, Stephen Bevan, Maria X. Sosa, Nanette R. Lee, Anuj Goel, Germaine C. Verwoert, Kjell Nikus, Helen R. Warren, May E. Montasser, Ren-Hua Chung, Francesco Gianfagna, Kristian Hveem, Rainer Rettig, Unnur Thorsteinsdottir, Lori L. Bonnycastle, Tim D. Spector, Paul W. Franks, Bamidele O. Tayo, Ilja M. Nolte, John Danesh, E. Shyong Tai, Mika Kivimäki, Devin Absher, Oddgeir L. Holmen, Per Eriksson, Pirjo Komulainen, Peter P. Pramstaller, Cameron D. Palmer, He Gao, Elena Tremoli, H.-Erich Wichmann, Myriam Fornage, Gyda Bjornsdottir, Afshin Parsa, Anders Hamsten, Terho Lehtimäki, Lasse Folkersen, Janine F. Felix, Anna F. Dominiczak, Hinco J. Gierman, Edward G. Lakatta, Alex S. F. Doney, Erik Ingelsson, Colin N. A. Palmer, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Vladan Mijatovic, Mark I. McCarthy, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Stefan Enroth, Mark J. Caulfield, Gudmar Thorleifsson, Tsun-Po Yang, François Mach, Cristen J. Willer, Claudia P. Cabrera, Aline Wagner, Michael Boehnke, Elias Salfati, Sekar Kathiresan, Ramachandran S. Vasan, Franco Giulianini, Harm-Jan Westra, Harold Snieder, Mark O. Goodarzi, M. Arfan Ikram, Fred Paccaud, Johannes H. Smit, Anna-Liisa Hartikainen, Xiaofeng Zhu, Markku Laakso, Ahmad Vaez, Albert Hofman, Amy J. Swift, Maria Hughes, I. Te Lee, Aroon D. Hingorani, Matti Uusitupa, Oscar H. Franco, Kenneth Rice, Veronique Vitart, Ross M. Fraser, Jouke-Jan Hottenga, Kari Stefansson, Dhananjay Vaidya, Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Saw Swee Hock School of Public Health, National University of Singapore (NUS), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Michigan System, Department of Computational Medicine and Bioinformatics (DCM&B), Queen Mary University of London (QMUL), GlaxoSmithKline, Glaxo Smith Kline, deCODE genetics [Reykjavik], University of Cambridge [UK] (CAM), University of Dundee, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Karolinska University Hospital [Stockholm], Umea University Hospital, Lund University [Lund], Queen's University [Belfast] (QUB), National Institutes of Health, Department of Genomics of Common Disease, Imperial College London, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), National Institute of Health and Welfare, Institute for Molecular Medicine Finland (FIMM), University College London Hospitals (UCLH), University Hospital of Heidelberg, Harbor UCLA Medical Center [Torrance, Ca.], University of Tampere, University of Verona (UNIVR), Uppsala University Hospital, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Stanford University School of Medicine [CA, USA], Medical School University of Athens, Partenaires INRAE, Children's Hospital Oakland Research Institute, Boston Children's Hospital, Broad Institute of Harvard and MIT, University of Copenhagen = Københavns Universitet (KU), Statens Serum Institut [Copenhagen], Framingham Heart Dis Epidemiol Study, Department of Psychiatry, VU University Medical Center [Amsterdam], National Heart, Lung and Blood Institute, Osong Health Technology Administration Complex, University of Pennsylvania, Department of Genetics, University of North Carolina at Chapel Hill (UNC), Loyola University [Chicago], Centre Hospitalier Universitaire Vaudois (CHUV), Hudson Alpha Institute for Biotechnology, Erasmus University Rotterdam, Department of Medical Sciences, Uppsala University, Università degli Studi di Milano [Milano] (UNIMI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], University of Lincoln, University of Washington [Seattle], Amgen Inc., The University of Texas Health Science Center at Houston (UTHealth), VU University Amsterdam, University of Dresden Medical School, Université de Lausanne (UNIL), Healthcare NHS Trust, National Health Research Institutes, National University Health System [Singapore] (NUHS), Duke-NUS Medical School [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National Human Genome Research Institute (NHGRI), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Radiology and nuclear medicine, EMGO - Mental health, Lin, Li, Mach, François, ProdInra, Migration, University of Oxford, Università degli studi di Verona = University of Verona (UNIVR), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano = University of Milan (UNIMI), Vrije Universiteit Amsterdam [Amsterdam] (VU), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO+ - Lifestyle, Overweight and Diabetes, Biological Psychology, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Danesh, John [0000-0003-1158-6791], Khaw, Kay-Tee [0000-0002-8802-2903], Markus, Hugh [0000-0002-9794-5996], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Medical Microbiology & Infectious Diseases, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Clinical Genetics, Biochemistry, National Institute for Health Research, and Medical Research Council (MRC)
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), CHROMATIN, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Blood Pressure, SUSCEPTIBILITY, Bioinformatics, Cardiovascular, Genome-wide association studies, Medical and Health Sciences, single nucleotide polymorphism, CHARGE-EchoGen consortium, GWAS, 2.1 Biological and endogenous factors, Aetiology, Cells, Cultured, African Continental Ancestry Group, Genetics & Heredity, Genetics, ddc:616, Kidney, Framingham Risk Score, Cultured, COMMON VARIANTS, 11 Medical And Health Sciences, Single Nucleotide, Biological Sciences, African Continental Ancestry Group/genetics, Asian Continental Ancestry Group/genetics, Blood Pressure/genetics, Genome-Wide Association Study, Humans, Hypertension/genetics, Hypertension/pathology, Microarray Analysis, Polymorphism, Single Nucleotide, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hypertension/genetics/pathology, Hypertension, Medical genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, TRAITS, Biotechnology, Asian Continental Ancestry Group, medicine.medical_specialty, CHARGE-EchoGen Consortium, Cells, Black People, BIOLOGY, Single-nucleotide polymorphism, Biology, Blood pressure, hypertension, genetics, single nucleotide polymorphism, GWAS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, CELL-TYPES, METAANALYSIS, Genetic association, Science & Technology, CHARGE-HF consortium, 06 Biological Sciences, Genetic architecture, 030104 developmental biology, Blood pressure, CHARGE-HF Consortium, ARTERIAL-HYPERTENSION, Developmental Biology
Abstract: To dissect the genetic architecture of blood pressure (BP) and assess how its elevation promotes downstream cardiovascular diseases, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry. Genotypes from an additional 140,886 individuals of European ancestry were used as validation for loci reaching genome-wide significance but without prior support in the literature. We identified 66 BP loci, of which 17 were novel and 15 harbored multiple distinct association signals, and which together explain up to 3.5% of BP variation. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in BP control through modulating blood vessel tone and fluid filtration across multiple tissues, not solely the kidney. Importantly, the 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent (South-Asian, East-Asian and African), confirming that these are ancestral physiological effects that arose prior to human migration out of Africa. The 66-SNP BP risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our data expand current knowledge of BP pathways, and also, highlight that BP regulation and its effects may occur in multiple organs and tissues beyond the classic renal system.
Published: 2016
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149. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study

Author: John F. Thompson, Marju Orho-Melander, Mary Susan Burnett, Jürgen Schrezenmeir, Nour Eddine El Mokhtari, Christopher J. O'Donnell, Philipp S. Wild, Christina Willenborg, Stacey Gabriel, Yvonne T. van der Schouw, Maja Barbalić, Alistair S. Hall, Christopher Newton-Cheh, Michael Boehnke, Sonia S. Anand, Diederick E. Grobbee, Andreas Ziegler, Asif Rasheed, Bruna Gigante, Anne Tybjærg-Hansen, Heribert Schunkert, Kiran Musunuru, Jaume Marrugat, Vincent Mooser, Markku S. Nieminen, Pascal P. McKeown, Nicola Martinelli, Olaf H. Klungel, George Hindy, Cristen J. Willer, Anthonius de Boer, Li Chen, Diego Ardissino, Marja-Liisa Lokki, Ron Do, Karen L. Mohlke, Elena Gonzalez, John F. Peden, Shaun Purcell, Diether Lambrechts, Ruth Frikke-Schmidt, Mark J. Daly, Ida Surakka, Aarti Surti, Frans Van de Werf, Gina M. Peloso, Serkalem Demissie, Jolanda M. A. Boer, Gonçalo R. Abecasis, Aki S. Havulinna, W. M. Monique Verschuren, Hugh Watkins, Danish Saleheen, Bas J M Peters, Nilesh J. Samani, Inke R. König, Domenico Girelli, Markus Perola, Paul I.W. de Bakker, Juha Sinisalo, James C. Engert, Alexandre F.R. Stewart, Unnur Thorsteinsdottir, Keith A.A. Fox, Stefan Blankenberg, Muredach P. Reilly, Joseph M. Devaney, Anke-Hilse Maitland-van der Zee, Klaus Berger, Eric Boerwinkle, Marcus Fischer, Gudmundur Thorgeirsson, John A. Spertus, Clara C. Elbers, Daniel J. Rader, Stefan Schreiber, Arne Schäfer, Tanja Zeller, Erik Ingelsson, Arne Schillert, Jemma C. Hopewell, John Danesh, Ian Buysschaert, Toby Johnson, Samuli Ripatti, David S. Siscovick, Eric B. Rimm, Jeanette Erdmann, Sekar Kathiresan, Christian Hengstenberg, Olle Melander, Mingyao Li, Gudmar Thorleifsson, Roberto Elosua, Hilma Holm, Vera H.M. Deneer, Ruth McPherson, Benjamin F. Voight, Candace Guiducci, N. Charlotte Onland-Moret, Philippe M. Frossard, James P. Pirruccello, Cisca Wijmenga, Majken K. Jensen, Leena Peltonen, Ulf de Faire, Christopher Patterson, Diana Rubin, David Altshuler, Jose M. Ordovas, Eric L. Ding, Thomas M. Morgan, Pieter Willem Kamphuisen, Noël P. Burtt, Patrick Diemert, Robert Roberts, Pier Mannuccio Mannucci, Stephen E. Epstein, Stephen M. Schwartz, Kim Overvad, Monika Stoll, Veikko Salomaa, Robert Clarke, Kari Stefansson, Marten H. Hofker, L. Adrienne Cupples, Faculteit Medische Wetenschappen/UMCG, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Cardiovascular Centre (CVC), and Vascular Ageing Programme (VAP)
Subjects: LOCI, Myocardial Infarction, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Gene Frequency, plasma HDL cholesterol, mendelian randomisation, MI, HDL cholesterol, single nucleotide polymorphism, Risk Factors, GENETIC-VARIANTS, ARTERY-DISEASE, Prospective Studies, Myocardial infarction, 0303 health sciences, myocardial infarction, ISCHEMIC CARDIOVASCULAR-DISEASE, General Medicine, 3. Good health, Cardiology, lipids (amino acids, peptides, and proteins), medicine.medical_specialty, Dalcetrapib, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, medicine, Humans, CORONARY-HEART-DISEASE, Genetic Predisposition to Disease, METAANALYSIS, 030304 developmental biology, BLOOD CHOLESTEROL, business.industry, Cholesterol, Cholesterol, HDL, Case-control study, Cholesterol, LDL, Lipase, Odds ratio, Mendelian Randomization Analysis, medicine.disease, ENDOTHELIAL LIPASE, ATHEROSCLEROSIS, chemistry, Case-Control Studies, business, HIGH-DENSITY-LIPOPROTEIN, Biomarkers, Evacetrapib
Abstract: BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)). INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. FUNDING: US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
Published: 2012
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150. Large-scale association analysis identifies new risk loci for coronary artery disease

Author: Benjamin F. Voight, Andrew D. Morris, G. Kees Hovingh, Anthony J. Balmforth, Hanneke Basart, Alistair S. Hall, Dominique Gauguier, Bok Ghee Han, Martina Müller-Nurasyid, Sarah Parish, Jarmo Virtamo, Christa Meisinger, Peter Wagner, George Dedoussis, Philipp S. Wild, Kari Stefansson, Jean-Baptiste Cazier, Kathleen Stirrups, Jiyoung Lee, Adrienne Cupples, Stavroula Kanoni, Danish Saleheen, Christian Hengstenberg, Svati H. Shah, Panos Deloukas, Anuj Goel, Stefan Blankenberg, Sian Tsung Tan, Alison H. Goodall, Tõnu Esko, Eric Boerwinkle, Gudmundur Thorgeirsson, Peter S. Braund, Joshua W. Knowles, Olle Melander, C. Ellen van der Schoot, Silke Rosinger, Maria Dimitriou, Wolfgang Koenig, Michael Boehnke, François Cambien, Per Lundmark, Dmitry Shungin, Wolfgang Kratzer, Pierre Zalloua, Reijo Laaksonen, Jean Ferrières, Villi Gudnason, Thorsten Kessler, Daniel J. Rader, Niclas Eriksson, Dominique Arveiler, Natalie R. van Zuydam, Kari Kuulasmaa, N. William Rayner, Sarah E. Hunt, Gudmar Thorleifsson, Jeanette Erdmann, Samuli Ripatti, Tsun-Po Yang, George A. Wells, Terho Lehtimäki, Kjell Nikus, Pierre Fontanillas, Jorg Hager, Martin Farrall, Jemma C. Hopewell, Frank Kee, Juha Sinisalo, Christopher J. O'Donnell, Asif Rasheed, Mika Kähönen, Genovefa Kolovou, Seraya Maouche, Suzanne Rafelt, Cordelia Langford, Winfried März, Leo-Pekka Lyytikäinen, Christina Willenborg, Weihua Zhang, Kati Kristiansson, Hyo-Soo Kim, Weang K. Ho, Jeong E. Park, Mohan U. Sivananthan, Moritz P. Rumpf, Markku Laakso, Klaus Stark, Philippe Amouyel, Paul W. Franks, Andres Metspalu, Anders Franco-Cereceda, Manjinder S. Sandhu, Nour Eddine El Mokhtari, Nicholas J. Wareham, Robert Roberts, Veikko Salomaa, Thomas Illig, Tomi Pastinen, Robert Clarke, Christof Burgdorf, Leif Groop, Devin Absher, Yangsoo Jang, Mark I. McCarthy, Bernhard O. Boehm, Per Eriksson, Nilesh J. Samani, Inke R. König, Stefan Schreiber, Karin Leander, Simone Claudi-Boehm, Ci Song, Benjamin A. Goldstein, Stephen E. Epstein, Andreas Ziegler, Stanley L. Hazen, Arne Schäfer, Elin Grundberg, Sekar Kathiresan, John R. Thompson, Unnur Thorsteinsdottir, Muredach P. Reilly, Heribert Schunkert, Rory Collins, Thomas Quertermous, Jong-Young Lee, John Danesh, John C. Chambers, Marco M Ferrario, Carlos Iribarren, Claudia Langenberg, Hilma Holm, Rona J. Strawbridge, Alan S. Go, Cristen J. Willer, Ron Do, Emmi Tikkanen, Abbas Dehghan, Evelin Mihailov, Lindsay L. Waite, Patrick Diemert, Willem H. Ouwehand, Eric E. Schadt, Diana Rubin, David Altshuler, Marcus E. Kleber, Markus Perola, Alexandre F.R. Stewart, Jaspal S. Kooner, Themistocles L. Assimes, Inês Barroso, Bruna Gigante, Göran Hallmans, Marja-Liisa Lokki, Aki S. Havulinna, Anders Hamsten, Agneta Siegbahn, Lasse Folkersen, Erik Ingelsson, Martina E. Zimmermann, Colin N. A. Palmer, Paolo Brambilla, Ann-Christine Syvänen, Alun Evans, Åsa Johansson, John F. Peden, Alex S. F. Doney, Hugh Watkins, Johanna Kuusisto, Anders Lundmark, David G. Cox, Hyun Min Kang, Lars Lind, Krista Fischer, Markku S. Nieminen, Annette Peters, Norman Klopp, Stefan Gustafsson, Lars Wallentin, Nancy L. Pedersen, David-Alexandre Trégouët, Ulf de Faire, Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, B, Stirrups, K, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Willer, C, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shungin, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Hunt, S, Kang, H, Illig, T, Kessler, T, Knowles, J, Kolovou, J, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Salomaa, V, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Wareham, N, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Franks, P, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Boehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Schunkert, H, Samani, N, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine
Subjects: Adult, Asian Continental Ancestry Group, Male, Candidate gene, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Population, European Continental Ancestry Group, Quantitative Trait Loci, CAD, Genome-wide association study, Single-nucleotide polymorphism, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Bioinformatics, Polymorphism, Single Nucleotide, Article, White People, coronary artery disease, risk loci, Cell Line, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Asian People, Risk Factors, medicine, Humans, genetics, Gene Regulatory Networks, Genetic Predisposition to Disease, cardiovascular diseases, Polymorphism, education, 030304 developmental biology, Genetic association, Aged, Genetics, 0303 health sciences, education.field_of_study, Adult, Aged, Asian Continental Ancestry Group, Cell Line, Coronary Artery Disease, genetics, European Continental Ancestry Group, genetics, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Single Nucleotide, Middle Aged, medicine.disease, 3. Good health, Female, Genome-Wide Association Study
Abstract: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r 2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways. © 2013 Nature America, Inc. All rights reserved.
Published: 2012
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