Search

Your search keyword '"Surakka, I."' showing total 2,848 results
Start Over "Surakka, I."

Refine your results

more »

more »

more »

more »

more »

more »
2,848 results on '"Surakka, I."'

1. Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.

Author

Das S, Finney AC, Anand SK, Rohilla S, Liu Y, Pandey N, Ghrayeb A, Kumar D, Nunez K, Liu Z, Arias F, Zhao Y, Pearson-Gallion BH, McKinney MP, Richard KSE, Gomez-Vidal JA, Abdullah CS, Cockerham ED, Eniafe J, Yurochko AD, Magdy T, Pattillo CB, Kevil CG, Razani B, Bhuiyan MS, Seeley EH, Galliano GE, Wei B, Tan L, Mahmud I, Surakka I, Garcia-Barrio MT, Lorenzi PL, Gottlieb E, Salido E, Zhang J, Orr AW, Liu W, Diaz-Gavilan M, Chen YE, Dhanesha N, Thevenot PT, Cohen AJ, Yurdagul A Jr, and Rom O

Subjects
Animals, Mice, Humans, Male, Transaminases metabolism, PPAR alpha metabolism, Hepatocytes metabolism, Mice, Inbred C57BL, Oxalates metabolism, Liver metabolism, Fatty Liver metabolism, Fatty Liver etiology
Abstract

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH., (© 2024. The Author(s).)

Published
2024
Full Text
View/download PDF

2. Exome wide association study for blood lipids in 1,158,017 individuals from diverse populations.

Author

Koyama S, Yu Z, Choi SH, Jurgens SJ, Selvaraj MS, Klarin D, Huffman JE, Clarke SL, Trinh MN, Ravi A, Dron JS, Spinks C, Surakka I, Bhatnagar A, Lannery K, Hornsby W, Damrauer SM, Chang KM, Lynch JA, Assimes TL, Tsao PS, Rader DJ, Cho K, Peloso GM, Ellinor PT, Sun YV, Wilson PW, Program MV, and Natarajan P

Abstract

Rare coding alleles play crucial roles in the molecular diagnosis of genetic diseases. However, the systemic identification of these alleles has been challenging due to their scarcity in the general population. Here, we discovered and characterized rare coding alleles contributing to genetic dyslipidemia, a principal risk for coronary artery disease, among over a million individuals combining three large contemporary genetic datasets (the Million Veteran Program, n = 634,535, UK Biobank, n = 431,178, and the All of Us Research Program, n = 92,304) totaling 1,158,017 multi-ancestral individuals. Unlike previous rare variant studies in lipids, this study included 238,243 individuals (20.6%) from non-European-like populations. Testing 2,997,401 rare coding variants from diverse backgrounds, we identified 800 exome-wide significant associations across 209 genes including 176 predicted loss of function and 624 missense variants. Among these exome-wide associations, 130 associations were driven by non-European-like populations. Associated alleles are highly enriched in functional variant classes, showed significant additive and recessive associations, exhibited similar effects across populations, and resolved pathogenicity for variants enriched in African or South-Asian populations. Furthermore, we identified 5 lipid-related genes associated with coronary artery disease (RORC, CFAP65, GTF2E2, PLCB3, and ZNF117) . Among them, RORC is a potentially novel therapeutic target through the down regulation of LDLC by its silencing. This study provides resources and insights for understanding causal mechanisms, quantifying the expressivity of rare coding alleles, and identifying novel drug targets across diverse populations., Competing Interests: Competing interest declaration D.K. is a scientific advisor and reports consulting fees from Bitterroot Bio, Inc unrelated to the present work. P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech / Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work.

Published
2024
Full Text
View/download PDF

3. Polygenic Score for the Prediction of Postoperative Nausea and Vomiting: A Retrospective Derivation and Validation Cohort Study.

Author

Douville NJ, Bastarache L, He J, Wu KH, Vanderwerff B, Bertucci-Richter E, Hornsby WE, Lewis A, Jewell ES, Kheterpal S, Shah N, Mathis M, Engoren MC, Douville CB, Surakka I, Willer C, and Kertai MD

Abstract

Background: Postoperative nausea and vomiting (PONV) is a key driver of unplanned admission and patient satisfaction following surgery. Because traditional risk factors do not completely explain variability in risk, we hypothesize that genetics may contribute to the overall risk for this complication. The objective of this research is to perform a genome-wide association study of PONV, derive a polygenic risk score for PONV, assess associations between the risk score and PONV in a validation cohort, and compare any genetic contributions to known clinical risks for PONV., Methods: Surgeries with integrated genetic and perioperative data performed under general anesthesia at Michigan Medicine and Vanderbilt University Medical Center were studied. PONV was defined as nausea or emesis occurring and documented in the PACU. In the Discovery Phase, genome-wide association studies were performed on each genetic cohort and the results were meta-analyzed. Next, in the Polygenic Phase, we assessed whether a polygenic score, derived from genome-wide association study in a derivation cohort from Vanderbilt University Medical Center, improved prediction within a validation cohort from Michigan Medicine, as quantified by discrimination (C-statistic) and net reclassification index., Results: Of 64,523 total patients, 5,703 developed PONV (8.8%). We identified 46 genetic variants exceeding P<1x10-5 threshold, occurring with minor allele frequency > 1%, and demonstrating concordant effects in both cohorts. Standardized polygenic score was associated with PONV in a basic model, controlling for age and sex, (aOR 1.027 per standard deviation increase in overall genetic risk, 95% CI 1.001-1.053, P=0.044), a model based on known clinical risks (aOR 1.029, 95% CI 1.003-1.055, P=0.030), and a full clinical regression, controlling for 21 demographic, surgical, and anesthetic factors, (aOR 1.029, 95% CI 1.002-1.056, P=0.033). The addition of polygenic score improved overall discrimination in models based on known clinical risk factors (c-statistic: 0.616 compared to 0.613, P=0.028) and improved net reclassification of 4.6% of cases., Conclusion: Standardized polygenic risk was associated with PONV in all three of our models, but the genetic influence was smaller than exerted by clinical risk factors. Specifically, a patient with a polygenic risk score > 1 standard deviation above the mean, has 2-3% greater odds of developing PONV when compared to the baseline population, which is at least an order of magnitude smaller than the increase associated with having prior PONV/motion sickness (55%), having a history of migraines (17%), or being female (83%), and is not clinically significant. Furthermore, the use of a polygenic risk score does not meaningfully improve discrimination compared to clinical risk factors and is not clinically useful., Competing Interests: Declarations of Interest: CD is a consultant to Exact Sciences and founder of Belay Diagnostics is compensated with income and equity. Exact Sciences is a molecular diagnostics company specializing in the detection of early-stage cancers. Belay Diagnostic is a platform for the detection of brain and spinal cord cancers using cerebrospinal fluid. The companies named above as well as other companies have licensed previously described technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins in accordance with its conflict-of-interest policies. CD’s involvement with both companies is unrelated to the scope of the research presented in this manuscript. CJW is currently employed by Regeneron Pharmaceuticals Inc and holds stock and options. KHW is currently employed by Regeneron Pharmaceutical Inc. MM received funding paid to the University of Michigan from Chiesi USA for work unrelated to the scope of the research presented in this manuscript., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Published
2024
Full Text
View/download PDF

4. Hypertriglyceridemia as a Key Contributor to Abdominal Aortic Aneurysm Development and Rupture: Insights from Genetic and Experimental Models.

Author

Liu Y, Wang H, Yu M, Cai L, Zhao Y, Cheng Y, Deng Y, Zhao Y, Lu H, Wu X, Zhao G, Xue C, Liu H, Surakka I, Schwendeman A, Lu HS, Daugherty A, Chang L, Zhang J, Temel RE, Chen YE, and Guo Y

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medications. This study integrated genetic, proteomic, and metabolomic data to identify causation between increased triglyceride (TG)-rich lipoproteins and AAA risk. Three hypertriglyceridemia mouse models were employed to test the hypothesis that increased plasma TG concentrations accelerate AAA development and rupture. In the angiotensin II-infusion AAA model, most Lpl -deficient mice with severely high plasma TG concentrations died of aortic rupture. Consistently, Apoa5 -deficient mice with moderately increased TG concentrations had accelerated AAA development, while human APOC3 transgenic mice with dramatically increased TG concentrations exhibited aortic dissection and rupture. Increased TG concentrations and palmitate inhibited lysyl oxidase maturation. Administration of antisense oligonucleotide targeting Angptl3 profoundly inhibited AAA progression in human APOC3 transgenic mice and Apoe -deficient mice. These results indicate that hypertriglyceridemia is a key contributor to AAA pathogenesis, highlighting the importance of triglyceride-rich lipoprotein management in treating AAA.

Published
2024
Full Text
View/download PDF

5. Genome-wide association analysis identifies six new loci associated with forced vital capacity

Author

Loth, DW, Artigas, MS, Gharib, SA, Wain, LV, Franceschini, N, Koch, B, Pottinger, TD, Smith, AV, Duan, Q, Oldmeadow, C, Lee, MK, Strachan, DP, James, AL, Huffman, JE, Vitart, V, Ramasamy, A, Wareham, NJ, Kaprio, J, Wang, XQ, Trochet, H, Kähönen, M, Flexeder, C, Albrecht, E, Lopez, LM, De Jong, K, Thyagarajan, B, Alves, AC, Enroth, S, Omenaas, E, Joshi, PK, Fall, T, Viñuela, A, Launer, LJ, Loehr, LR, Fornage, M, Li, G, Wilk, JB, Tang, W, Manichaikul, A, Lahousse, L, Harris, TB, North, KE, Rudnicka, AR, Hui, J, Gu, X, Lumley, T, Wright, AF, Hastie, ND, Campbell, S, Kumar, R, Pin, I, Scott, RA, Pietiläinen, KH, Surakka, I, Liu, Y, Holliday, EG, Schulz, H, Heinrich, J, Davies, G, Vonk, JM, Wojczynski, M, Pouta, A, Johansson, A, Wild, SH, Ingelsson, E, Rivadeneira, F, Völzke, H, Hysi, PG, Eiriksdottir, G, Morrison, AC, Rotter, JI, Gao, W, Postma, DS, White, WB, Rich, SS, Hofman, A, Aspelund, T, Couper, D, Smith, LJ, Psaty, BM, Lohman, K, Burchard, EG, Uitterlinden, AG, Garcia, M, Joubert, BR, McArdle, WL, Musk, AB, Hansel, N, Heckbert, SR, Zgaga, L, Van Meurs, JBJ, Navarro, P, Rudan, I, Oh, YM, Redline, S, Jarvis, DL, Zhao, JH, Rantanen, T, O'Connor, GT, and Ripatti, S

Subjects
Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10-8) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.© 2014 Nature America, Inc. All rights reserved.

Published
2014

6. Modification of coronary artery disease clinical risk factors by coronary artery disease polygenic risk score.

Author

Truong B, Ruan Y, Haidermota S, Patel A, Surakka I, Hornsby W, Koyama S, Lee SH, and Natarajan P

Subjects
Humans, Male, Female, Middle Aged, Risk Factors, United Kingdom epidemiology, Proportional Hazards Models, Aged, Multifactorial Inheritance genetics, Genome-Wide Association Study, Adult, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 epidemiology, White People genetics, Incidence, Risk Assessment, Heart Disease Risk Factors, Genetic Risk Score, Coronary Artery Disease genetics, Coronary Artery Disease epidemiology
Abstract

Background: The extent to which the relationships between clinical risk factors and coronary artery disease (CAD) are altered by CAD polygenic risk score (PRS) is not well understood. Here, we determine whether the interactions between clinical risk factors and CAD PRS further explain risk for incident CAD., Methods: Participants were of European ancestry from the UK Biobank without prevalent CAD. An externally trained genome-wide CAD PRS was generated and then applied. Clinical risk factors were ascertained at baseline. Cox proportional hazards models were fitted to examine the incident CAD effects of CAD PRS, risk factors, and their interactions. Next, the PRS and risk factors were stratified to investigate the attributable risk of clinical risk factors., Findings: A total of 357,144 individuals of European ancestry without prevalent CAD were included. During a median of 11.1 years of follow-up (interquartile range 10.4-14.1 years), CAD PRS was associated with 1.35-fold (95% confidence interval [CI] 1.332-1.368) risk per SD for incident CAD. The prognostic relevance of the following risk factors was relatively diminished for those with high CAD PRS on a continuous scale: type 2 diabetes (hazard ratio [HR] interaction 0.91, 95% CI interaction 0.88-0.94), increased body mass index (HR interaction 0.97, 95% CI interaction 0.96-0.98), and increased C-reactive protein (HR interaction 0.98, 95% CI interaction 0.96-0.99). However, a high CAD PRS yielded joint risk increases with low-density lipoprotein cholesterol (HR interaction 1.05, 95% CI interaction 1.04-1.06) and total cholesterol (HR interaction 1.05, 95% CI interaction 1.03-1.06)., Conclusion: The CAD PRS is associated with incident CAD, and its application improves the prognostic relevance of several clinical risk factors., Funding: P.N. (R01HL127564, R01HL151152, and U01HG011719) is supported by the National Institutes of Health., Competing Interests: Declaration of interests P.N. reports grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, Novartis, and TenSixteen Bio; equity in geneXwell, TenSixteen Bio, and Vertex; and spousal employment at Vertex. P.N. is a cofounder of TenSixteen Bio, a company focusing on somatic mutations in blood cells to reduce risks for blood cancer and atherosclerotic cardiovascular disease; his interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
Full Text
View/download PDF

7. Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.

Author

Sargurupremraj M, Soumaré A, Bis JC, Surakka I, Jürgenson T, Joly P, Knol MJ, Wang R, Yang Q, Satizabal CL, Gudjonsson A, Mishra A, Bouteloup V, Phuah CL, van Duijn CM, Cruchaga C, Dufouil C, Chêne G, Lopez OL, Psaty BM, Tzourio C, Amouyel P, Adams HH, Jacqmin-Gadda H, Ikram MA, Gudnason V, Milani L, Winsvold BS, Hveem K, Matthews PM, Longstreth WT, Seshadri S, Launer LJ, and Debette S

Subjects
Humans, Female, Male, Aged, Genome-Wide Association Study, Mendelian Randomization Analysis, Alzheimer Disease genetics, Alzheimer Disease epidemiology, Stroke genetics, Stroke epidemiology, Risk Factors, Genetic Predisposition to Disease, Aged, 80 and over, Prospective Studies, Cerebral Small Vessel Diseases genetics, Cerebral Small Vessel Diseases epidemiology, Dementia genetics, Dementia epidemiology, Blood Pressure genetics
Abstract

Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain., Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases., Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022., Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations., Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses., Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke., Conclusions: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

Published
2024
Full Text
View/download PDF

8. Author Correction: New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Author

Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD, Melbourne CA, Batini C, Fawcett KA, Song K, Sakornsakolpat P, Li X, Boxall R, Reeve NF, Obeidat M, Zhao JH, Wielscher M, Weiss S, Kentistou KA, Cook JP, Sun BB, Zhou J, Hui J, Karrasch S, Imboden M, Harris SE, Marten J, Enroth S, Kerr SM, Surakka I, Vitart V, Lehtimäki T, Allen RJ, Bakke PS, Beaty TH, Bleecker ER, Bossé Y, Brandsma CA, Chen Z, Crapo JD, Danesh J, DeMeo DL, Dudbridge F, Ewert R, Gieger C, Gulsvik A, Hansell AL, Hao K, Hoffman JD, Hokanson JE, Homuth G, Joshi PK, Joubert P, Langenberg C, Li X, Li L, Lin K, Lind L, Locantore N, Luan J, Mahajan A, Maranville JC, Murray A, Nickle DC, Packer R, Parker MM, Paynton ML, Porteous DJ, Prokopenko D, Qiao D, Rawal R, Runz H, Sayers I, Sin DD, Smith BH, Artigas MS, Sparrow D, Tal-Singer R, Timmers PRHJ, Van den Berge M, Whittaker JC, Woodruff PG, Yerges-Armstrong LM, Troyanskaya OG, Raitakari OT, Kähönen M, Polašek O, Gyllensten U, Rudan I, Deary IJ, Probst-Hensch NM, Schulz H, James AL, Wilson JF, Stubbe B, Zeggini E, Jarvelin MR, Wareham N, Silverman EK, Hayward C, Morris AP, Butterworth AS, Scott RA, Walters RG, Meyers DA, Cho MH, Strachan DP, Hall IP, Tobin MD, and Wain LV

Published
2024
Full Text
View/download PDF

9. Genome-wide association studies reveal differences in genetic susceptibility between single events vs. recurrent events of atrial fibrillation and myocardial infarction: the HUNT study.

Author

Hall M, Skogholt AH, Surakka I, Dalen H, and Almaas E

Abstract

Genetic research into atrial fibrillation (AF) and myocardial infarction (MI) has predominantly focused on comparing afflicted individuals with their healthy counterparts. However, this approach lacks granularity, thus overlooking subtleties within patient populations. In this study, we explore the distinction between AF and MI patients who experience only a single disease event and those experiencing recurrent events. Integrating hospital records, questionnaire data, clinical measurements, and genetic data from more than 500,000 HUNT and United Kingdom Biobank participants, we compare both clinical and genetic characteristics between the two groups using genome-wide association studies (GWAS) meta-analyses, phenome-wide association studies (PheWAS) analyses, and gene co-expression networks. We found that the two groups of patients differ in both clinical characteristics and genetic risks. More specifically, recurrent AF patients are significantly younger and have better baseline health, in terms of reduced cholesterol and blood pressure, than single AF patients. Also, the results of the GWAS meta-analysis indicate that recurrent AF patients seem to be at greater genetic risk for recurrent events. The PheWAS and gene co-expression network analyses highlight differences in the functions associated with the sets of single nucleotide polymorphisms (SNPs) and genes for the two groups. However, for MI patients, we found that those experiencing single events are significantly younger and have better baseline health than those with recurrent MI, yet they exhibit higher genetic risk. The GWAS meta-analysis mostly identifies genetic regions uniquely associated with single MI, and the PheWAS analysis and gene co-expression networks support the genetic differences between the single MI and recurrent MI groups. In conclusion, this work has identified novel genetic regions uniquely associated with single MI and related PheWAS analyses, as well as gene co-expression networks that support the genetic differences between the patient subgroups of single and recurrent occurrence for both MI and AF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Hall, Skogholt, Surakka, Dalen and Almaas.)

Published
2024
Full Text
View/download PDF

10. A genome-wide association study provides insights into the genetic etiology of 57 essential and non-essential trace elements in humans.

Author

Moksnes MR, Hansen AF, Wolford BN, Thomas LF, Rasheed H, Simić A, Bhatta L, Brantsæter AL, Surakka I, Zhou W, Magnus P, Njølstad PR, Andreassen OA, Syversen T, Zheng J, Fritsche LG, Evans DM, Warrington NM, Nøst TH, Åsvold BO, Flaten TP, Willer CJ, Hveem K, and Brumpton BM

Subjects
Male, Humans, Genome-Wide Association Study, Zinc, Manganese, Trace Elements metabolism, Selenium analysis
Abstract

Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study of 57 essential and non-essential trace elements. We perform genome-wide association meta-analyses of 14 trace elements in up to 6564 Scandinavian whole blood samples, and genome-wide association studies of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identify 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide association meta-analyses. In HUNT, several genome-wide significant loci are also indicated for other trace elements. Using two-sample Mendelian randomization, we find several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our current understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health., (© 2024. The Author(s).)

Published
2024
Full Text
View/download PDF

11. Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation.

Author

Lo Faro V, Bhattacharya A, Zhou W, Zhou D, Wang Y, Läll K, Kanai M, Lopera-Maya E, Straub P, Pawar P, Tao R, Zhong X, Namba S, Sanna S, Nolte IM, Okada Y, Ingold N, MacGregor S, Snieder H, Surakka I, Shortt J, Gignoux C, Rafaels N, Crooks K, Verma A, Verma SS, Guare L, Rader DJ, Willer C, Martin AR, Brantley MA Jr, Gamazon ER, Jansonius NM, Joos K, Cox NJ, and Hirbo J

Subjects
Male, Female, Humans, Polymorphism, Single Nucleotide, Cell Proliferation, Biology, Genetic Predisposition to Disease genetics, Glaucoma, Open-Angle genetics, Glaucoma, Open-Angle epidemiology
Abstract

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene-enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of SIX6 and CDKN2B-AS1 loci in human GTEx data and across large electronic health records showing interaction between SIX6 gene and causal variants in the chr9p21.3 locus, with expression effect on CDKN2A/B. Our results suggest that some POAG risk variants may be ancestry specific, sex specific, or both, and support the contribution of genes involved in programmed cell death in POAG pathogenesis., Competing Interests: Declaration of interests E.R.G. received an honorarium from the journal Circulation Research of the American Heart Association as a member of the Editorial Board. S.M. is a co-founder and holds stock in Seonix Pty Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
Full Text
View/download PDF

12. Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.

Author

Roychowdhury T, Klarin D, Levin MG, Spin JM, Rhee YH, Deng A, Headley CA, Tsao NL, Gellatly C, Zuber V, Shen F, Hornsby WE, Laursen IH, Verma SS, Locke AE, Einarsson G, Thorleifsson G, Graham SE, Dikilitas O, Pattee JW, Judy RL, Pauls-Verges F, Nielsen JB, Wolford BN, Brumpton BM, Dilmé J, Peypoch O, Juscafresa LC, Edwards TL, Li D, Banasik K, Brunak S, Jacobsen RL, Garcia-Barrio MT, Zhang J, Rasmussen LM, Lee R, Handa A, Wanhainen A, Mani K, Lindholt JS, Obel LM, Strauss E, Oszkinis G, Nelson CP, Saxby KL, van Herwaarden JA, van der Laan SW, van Setten J, Camacho M, Davis FM, Wasikowski R, Tsoi LC, Gudjonsson JE, Eliason JL, Coleman DM, Henke PK, Ganesh SK, Chen YE, Guan W, Pankow JS, Pankratz N, Pedersen OB, Erikstrup C, Tang W, Hveem K, Gudbjartsson D, Gretarsdottir S, Thorsteinsdottir U, Holm H, Stefansson K, Ferreira MA, Baras A, Kullo IJ, Ritchie MD, Christensen AH, Iversen KK, Eldrup N, Sillesen H, Ostrowski SR, Bundgaard H, Ullum H, Burgess S, Gill D, Gallagher K, Sabater-Lleal M, Surakka I, Jones GT, Bown MJ, Tsao PS, Willer CJ, and Damrauer SM

Subjects
Humans, Animals, Mice, Proprotein Convertase 9 genetics, Proprotein Convertase 9 metabolism, Subtilisin, Proprotein Convertases, Genome-Wide Association Study, Aortic Aneurysm, Abdominal genetics
Abstract

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Published
2023
Full Text
View/download PDF

13. Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.

Author

Beaumont RN, Flatley C, Vaudel M, Wu X, Chen J, Moen GH, Skotte L, Helgeland Ø, Solé-Navais P, Banasik K, Albiñana C, Ronkainen J, Fadista J, Stinson SE, Trajanoska K, Wang CA, Westergaard D, Srinivasan S, Sánchez-Soriano C, Bilbao JR, Allard C, Groleau M, Kuulasmaa T, Leirer DJ, White F, Jacques PÉ, Cheng H, Hao K, Andreassen OA, Åsvold BO, Atalay M, Bhatta L, Bouchard L, Brumpton BM, Brunak S, Bybjerg-Grauholm J, Ebbing C, Elliott P, Engelbrechtsen L, Erikstrup C, Estarlich M, Franks S, Gaillard R, Geller F, Grove J, Hougaard DM, Kajantie E, Morgen CS, Nohr EA, Nyegaard M, Palmer CNA, Pedersen OB, Rivadeneira F, Sebert S, Shields BM, Stoltenberg C, Surakka I, Thørner LW, Ullum H, Vaarasmaki M, Vilhjalmsson BJ, Willer CJ, Lakka TA, Gybel-Brask D, Bustamante M, Hansen T, Pearson ER, Reynolds RM, Ostrowski SR, Pennell CE, Jaddoe VWV, Felix JF, Hattersley AT, Melbye M, Lawlor DA, Hveem K, Werge T, Nielsen HS, Magnus P, Evans DM, Jacobsson B, Järvelin MR, Zhang G, Hivert MF, Johansson S, Freathy RM, Feenstra B, and Njølstad PR

Subjects
Female, Humans, Pregnancy, Birth Weight genetics, Fetal Development genetics, Insulin, Male, Genome-Wide Association Study, Placenta metabolism
Abstract

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth., (© 2023. The Author(s).)

Published
2023
Full Text
View/download PDF

14. Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study.

Author

Cho SMJ, Koyama S, Honigberg MC, Surakka I, Haidermota S, Ganesh S, Patel AP, Bhattacharya R, Lee H, Kim HC, and Natarajan P

Subjects
Adult, Middle Aged, Humans, Cholesterol, HDL, Cohort Studies, Risk Factors, C-Reactive Protein, Lipoprotein(a) genetics, Life Style, Coronary Artery Disease epidemiology, Coronary Artery Disease genetics
Abstract

Aims: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence., Methods and Results: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686)., Conclusion: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2023
Full Text
View/download PDF

15. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Kanoni, S., Graham, S.E., Wang, Yuxuan, Surakka, I., Ramdas, S., Zhu, X, Clarke, S.L., Bhatti, K.F., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Zajac, G.J.M., Wu, K.H., Ntalla, I., Hui, Q., Klarin, D., Hilliard, A.T., Wang, Zeyuan, Xue, C., Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Hwang, M.Y., Han, S., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W, Brumpton, B.M., Rasheed, H., Havulinna, A.S., Veturi, Y., Pacheco, J.A., Rosenthal, E.A., Lingren, T., Feng, Q., Kullo, I.J., Narita, A., Takayama, J., Martin, H.C., Hunt, K.A., Trivedi, B., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Rasheed, A., Hindy, G., Faul, J.D., Zhao, Wei, Weir, D.R., Turman, C., Huang, H., Graff, M, Choudhury, A., Sengupta, D., Mahajan, A., Brown, M.R., Zhang, W, Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J, Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Yousri, N.A., Mitchell, R.E., Chai, J.F., Aadahl, M., Bjerregaard, A.A., Yao, J., Manichaikul, A., Hwu, C.M., Hung, Y.J., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Mauro, P., Galesloot, T.E., Lores-Motta, L., Pauper, M., Hollander, A.I. den, Kiemeney, L.A.L.M., Graaf, J. de, Assimes, T.L., Peloso, G.M., Kanoni, S., Graham, S.E., Wang, Yuxuan, Surakka, I., Ramdas, S., Zhu, X, Clarke, S.L., Bhatti, K.F., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Zajac, G.J.M., Wu, K.H., Ntalla, I., Hui, Q., Klarin, D., Hilliard, A.T., Wang, Zeyuan, Xue, C., Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Hwang, M.Y., Han, S., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W, Brumpton, B.M., Rasheed, H., Havulinna, A.S., Veturi, Y., Pacheco, J.A., Rosenthal, E.A., Lingren, T., Feng, Q., Kullo, I.J., Narita, A., Takayama, J., Martin, H.C., Hunt, K.A., Trivedi, B., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Rasheed, A., Hindy, G., Faul, J.D., Zhao, Wei, Weir, D.R., Turman, C., Huang, H., Graff, M, Choudhury, A., Sengupta, D., Mahajan, A., Brown, M.R., Zhang, W, Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J, Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Yousri, N.A., Mitchell, R.E., Chai, J.F., Aadahl, M., Bjerregaard, A.A., Yao, J., Manichaikul, A., Hwu, C.M., Hung, Y.J., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Mauro, P., Galesloot, T.E., Lores-Motta, L., Pauper, M., Hollander, A.I. den, Kiemeney, L.A.L.M., Graaf, J. de, Assimes, T.L., and Peloso, G.M.

Abstract

Item does not contain fulltext, BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022

16. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

Author

Ramdas, S., Judd, J., Graham, S.E., Kanoni, S., Wang, Y, Surakka, I., Wenz, B., Clarke, S.L., Chesi, A., Wells, A., Bhatti, K.F., Vedantam, S., Locke, A.E., Marouli, E., Zajac, G.J.M., Wu, K.H., Ntalla, I., Hui, Q., Klarin, D., Hilliard, A.T., Wang, Z, Xue, C., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Hwang, M.Y., Han, S., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W, Brumpton, B.M., Rasheed, H., Havulinna, A.S., Veturi, Y., Pacheco, J.A., Rosenthal, E.A., Lingren, T., Feng, Q., Kullo, I.J., Narita, A., Takayama, J., Martin, H.C., Hunt, K.A., Trivedi, B., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Rasheed, A., Hindy, G., Faul, J.D., Zhao, W, Weir, D.R., Turman, C., Huang, H., Graff, Mariaelisa, Choudhury, A., Sengupta, D., Mahajan, A., Brown, M.R., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J, Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Bjerregaard, A.A., Yao, J., Manichaikul, A., Lee, W.J., Hsiung, C.A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Galesloot, T.E., Lores de Motta, L., Pauper, M., Hollander, A.I. den, Kiemeney, L.A.L.M., Zhu, Xiang, Brown, C.D., Ramdas, S., Judd, J., Graham, S.E., Kanoni, S., Wang, Y, Surakka, I., Wenz, B., Clarke, S.L., Chesi, A., Wells, A., Bhatti, K.F., Vedantam, S., Locke, A.E., Marouli, E., Zajac, G.J.M., Wu, K.H., Ntalla, I., Hui, Q., Klarin, D., Hilliard, A.T., Wang, Z, Xue, C., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Hwang, M.Y., Han, S., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W, Brumpton, B.M., Rasheed, H., Havulinna, A.S., Veturi, Y., Pacheco, J.A., Rosenthal, E.A., Lingren, T., Feng, Q., Kullo, I.J., Narita, A., Takayama, J., Martin, H.C., Hunt, K.A., Trivedi, B., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Rasheed, A., Hindy, G., Faul, J.D., Zhao, W, Weir, D.R., Turman, C., Huang, H., Graff, Mariaelisa, Choudhury, A., Sengupta, D., Mahajan, A., Brown, M.R., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J, Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Bjerregaard, A.A., Yao, J., Manichaikul, A., Lee, W.J., Hsiung, C.A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Galesloot, T.E., Lores de Motta, L., Pauper, M., Hollander, A.I. den, Kiemeney, L.A.L.M., Zhu, Xiang, and Brown, C.D.

Abstract

Item does not contain fulltext, A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Published
2022

17. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Author

Lahti, J., Tuominen, S., Yang, Q., Pergola, G., Ahmad, S., Amin, N., Armstrong, N.J., Beiser, A., Bey, K., Bis, J.C., Boerwinkle, E., Bressler, J., Campbell, A., Campbell, H., Chen, Q., Corley, J., Cox, S.R., Davies, G., De Jager, P.L., Derks, E.M., Faul, J.D., Fitzpatrick, A.L., Fohner, A.E., Ford, I., Fornage, M., Gerring, Z., Grabe, H.J., Grodstein, F., Gudnason, V., Simonsick, E., Holliday, E.G., Joshi, P.K., Kajantie, E., Kaprio, J., Karell, P., Kleineidam, L., Knol, M.J., Kochan, N.A., Kwok, J.B., Leber, M., Lam, M., Lee, T., Li, S., Loukola, A., Luck, T., Marioni, R.E., Mather, K.A., Medland, S., Mirza, S.S., Nalls, M.A., Nho, K., O’Donnell, A., Oldmeadow, C., Painter, J., Pattie, A., Reppermund, S., Risacher, S.L., Rose, R.J., Sadashivaiah, V., Scholz, M., Satizabal, C.L., Schofield, P.W., Schraut, K.E., Scott, R.J., Simino, J., Smith, A.V., Smith, J.A., Stott, D.J., Surakka, I., Teumer, A., Thalamuthu, A., Trompet, S., Turner, S.T., van der Lee, S.J., Villringer, A., Völker, U., Wilson, R.S., Wittfeld, K., Vuoksimaa, E., Xia, R., Yaffe, K., Yu, L., Zare, H., Zhao, W., Ames, D., Attia, J., Bennett, D.A., Brodaty, H., Chasman, D.I., Goldman, A.L., Hayward, C., Ikram, M.A., Jukema, J.W., Kardia, S.L.R., Lencz, T., Loeffler, M., Mattay, V.S., Palotie, A., Psaty, B.M., Ramirez, A., Ridker, P.M., Riedel-Heller, S.G., Sachdev, P.S., Saykin, A.J., Scherer, M., Schofield, P.R., Sidney, S., Starr, J.M., Trollor, J., Ulrich, W., Wagner, M., Weir, D.R., Wilson, J.F., Wright, M.J., Weinberger, D.R., Debette, S., Eriksson, J.G., Mosley, T.H., Launer, L.J., van Duijn, C.M., Deary, I.J., Seshadri, S., Räikkönen, K., Lahti, J., Tuominen, S., Yang, Q., Pergola, G., Ahmad, S., Amin, N., Armstrong, N.J., Beiser, A., Bey, K., Bis, J.C., Boerwinkle, E., Bressler, J., Campbell, A., Campbell, H., Chen, Q., Corley, J., Cox, S.R., Davies, G., De Jager, P.L., Derks, E.M., Faul, J.D., Fitzpatrick, A.L., Fohner, A.E., Ford, I., Fornage, M., Gerring, Z., Grabe, H.J., Grodstein, F., Gudnason, V., Simonsick, E., Holliday, E.G., Joshi, P.K., Kajantie, E., Kaprio, J., Karell, P., Kleineidam, L., Knol, M.J., Kochan, N.A., Kwok, J.B., Leber, M., Lam, M., Lee, T., Li, S., Loukola, A., Luck, T., Marioni, R.E., Mather, K.A., Medland, S., Mirza, S.S., Nalls, M.A., Nho, K., O’Donnell, A., Oldmeadow, C., Painter, J., Pattie, A., Reppermund, S., Risacher, S.L., Rose, R.J., Sadashivaiah, V., Scholz, M., Satizabal, C.L., Schofield, P.W., Schraut, K.E., Scott, R.J., Simino, J., Smith, A.V., Smith, J.A., Stott, D.J., Surakka, I., Teumer, A., Thalamuthu, A., Trompet, S., Turner, S.T., van der Lee, S.J., Villringer, A., Völker, U., Wilson, R.S., Wittfeld, K., Vuoksimaa, E., Xia, R., Yaffe, K., Yu, L., Zare, H., Zhao, W., Ames, D., Attia, J., Bennett, D.A., Brodaty, H., Chasman, D.I., Goldman, A.L., Hayward, C., Ikram, M.A., Jukema, J.W., Kardia, S.L.R., Lencz, T., Loeffler, M., Mattay, V.S., Palotie, A., Psaty, B.M., Ramirez, A., Ridker, P.M., Riedel-Heller, S.G., Sachdev, P.S., Saykin, A.J., Scherer, M., Schofield, P.R., Sidney, S., Starr, J.M., Trollor, J., Ulrich, W., Wagner, M., Weir, D.R., Wilson, J.F., Wright, M.J., Weinberger, D.R., Debette, S., Eriksson, J.G., Mosley, T.H., Launer, L.J., van Duijn, C.M., Deary, I.J., Seshadri, S., and Räikkönen, K.

Abstract

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Published
2022

18. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Author

Lahti, J, Tuominen, S, Yang, Q, Pergola, G, Ahmad, S, Amin, N, Armstrong, NJ, Beiser, A, Bey, K, Bis, JC, Boerwinkle, E, Bressler, J, Campbell, A, Campbell, H, Chen, Q, Corley, J, Cox, SR, Davies, G, De Jager, PL, Derks, EM, Faul, JD, Fitzpatrick, AL, Fohner, AE, Ford, I, Fornage, M, Gerring, Z, Grabe, HJ, Grodstein, F, Gudnason, V, Simonsick, E, Holliday, EG, Joshi, PK, Kajantie, E, Kaprio, J, Karell, P, Kleineidam, L, Knol, MJ, Kochan, NA, Kwok, JB, Leber, M, Lam, M, Lee, T, Li, S, Loukola, A, Luck, T, Marioni, RE, Mather, KA, Medland, S, Mirza, SS, Nalls, MA, Nho, K, O'Donnell, A, Oldmeadow, C, Painter, J, Pattie, A, Reppermund, S, Risacher, SL, Rose, RJ, Sadashivaiah, V, Scholz, M, Satizabal, CL, Schofield, PW, Schraut, KE, Scott, RJ, Simino, J, Smith, AV, Smith, JA, Stott, DJ, Surakka, I, Teumer, A, Thalamuthu, A, Trompet, S, Turner, ST, van der Lee, SJ, Villringer, A, Voelker, U, Wilson, RS, Wittfeld, K, Vuoksimaa, E, Xia, R, Yaffe, K, Yu, L, Zare, H, Zhao, W, Ames, D, Attia, J, Bennett, DA, Brodaty, H, Chasman, DI, Goldman, AL, Hayward, C, Ikram, MA, Jukema, JW, Kardia, SLR, Lencz, T, Loeffler, M, Mattay, VS, Palotie, A, Psaty, BM, Ramirez, A, Ridker, PM, Riedel-Heller, SG, Sachdev, PS, Saykin, AJ, Scherer, M, Schofield, PR, Sidney, S, Starr, JM, Trollor, J, Ulrich, W, Wagner, M, Weir, DR, Wilson, JF, Wright, MJ, Weinberger, DR, Debette, S, Eriksson, JG, Mosley, TH, Launer, LJ, van Duijn, CM, Deary, IJ, Seshadri, S, Raikkonen, K, Lahti, J, Tuominen, S, Yang, Q, Pergola, G, Ahmad, S, Amin, N, Armstrong, NJ, Beiser, A, Bey, K, Bis, JC, Boerwinkle, E, Bressler, J, Campbell, A, Campbell, H, Chen, Q, Corley, J, Cox, SR, Davies, G, De Jager, PL, Derks, EM, Faul, JD, Fitzpatrick, AL, Fohner, AE, Ford, I, Fornage, M, Gerring, Z, Grabe, HJ, Grodstein, F, Gudnason, V, Simonsick, E, Holliday, EG, Joshi, PK, Kajantie, E, Kaprio, J, Karell, P, Kleineidam, L, Knol, MJ, Kochan, NA, Kwok, JB, Leber, M, Lam, M, Lee, T, Li, S, Loukola, A, Luck, T, Marioni, RE, Mather, KA, Medland, S, Mirza, SS, Nalls, MA, Nho, K, O'Donnell, A, Oldmeadow, C, Painter, J, Pattie, A, Reppermund, S, Risacher, SL, Rose, RJ, Sadashivaiah, V, Scholz, M, Satizabal, CL, Schofield, PW, Schraut, KE, Scott, RJ, Simino, J, Smith, AV, Smith, JA, Stott, DJ, Surakka, I, Teumer, A, Thalamuthu, A, Trompet, S, Turner, ST, van der Lee, SJ, Villringer, A, Voelker, U, Wilson, RS, Wittfeld, K, Vuoksimaa, E, Xia, R, Yaffe, K, Yu, L, Zare, H, Zhao, W, Ames, D, Attia, J, Bennett, DA, Brodaty, H, Chasman, DI, Goldman, AL, Hayward, C, Ikram, MA, Jukema, JW, Kardia, SLR, Lencz, T, Loeffler, M, Mattay, VS, Palotie, A, Psaty, BM, Ramirez, A, Ridker, PM, Riedel-Heller, SG, Sachdev, PS, Saykin, AJ, Scherer, M, Schofield, PR, Sidney, S, Starr, JM, Trollor, J, Ulrich, W, Wagner, M, Weir, DR, Wilson, JF, Wright, MJ, Weinberger, DR, Debette, S, Eriksson, JG, Mosley, TH, Launer, LJ, van Duijn, CM, Deary, IJ, Seshadri, S, and Raikkonen, K

Abstract

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Published
2022

19. Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.

Author

Sargurupremraj M, Soumare A, Bis JC, Surakka I, Jurgenson T, Joly P, Knol MJ, Wang R, Yang Q, Satizabal CL, Gudjonsson A, Mishra A, Bouteloup V, Phuah CL, van Duijn CM, Cruchaga C, Dufouil C, Chêne G, Lopez O, Psaty BM, Tzourio C, Amouyel P, Adams HH, Jacqmin-Gadda H, Ikram MA, Gudnason V, Milani L, Winsvold BS, Hveem K, Matthews PM, Longstreth WT, Seshadri S, Launer LJ, and Debette S

Abstract

Importance: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear., Objective: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia., Design Setting and Participants: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022., Exposures: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke., Main Outcomes and Measures: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD meta , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses., Results: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD meta (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD meta , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke., Conclusion: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

Published
2023
Full Text
View/download PDF

20. Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program.

Author

Klarin D, Devineni P, Sendamarai AK, Angueira AR, Graham SE, Shen YH, Levin MG, Pirruccello JP, Surakka I, Karnam PR, Roychowdhury T, Li Y, Wang M, Aragam KG, Paruchuri K, Zuber V, Shakt GE, Tsao NL, Judy RL, Vy HMT, Verma SS, Rader DJ, Do R, Bavaria JE, Nadkarni GN, Ritchie MD, Burgess S, Guo DC, Ellinor PT, LeMaire SA, Milewicz DM, Willer CJ, Natarajan P, Tsao PS, Pyarajan S, and Damrauer SM

Subjects
Humans, Genome-Wide Association Study, Pedigree, Veterans, Aortic Aneurysm, Thoracic genetics, Aortic Dissection genetics
Abstract

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Published
2023
Full Text
View/download PDF

21. Multi-ancestry meta-analysis identifies 5 novel loci for ischemic stroke and reveals heterogeneity of effects between sexes and ancestries.

Author

Surakka I, Wu KH, Hornsby W, Wolford BN, Shen F, Zhou W, Huffman JE, Pandit A, Hu Y, Brumpton B, Skogholt AH, Gabrielsen ME, Walters RG, Hveem K, Kooperberg C, Zöllner S, Wilson PWF, Sutton NR, Daly MJ, Neale BM, and Willer CJ

Abstract

Stroke is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, possibly due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetics of ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI) and further combined the results with previously published MegaStroke. Five novel loci for ischemic stroke ( LAMC1 , CALCRL , PLSCR1 , CDKN1A , and SWAP70 ) were identified after replication in four additional datasets. One previously reported locus showed significant ancestry heterogeneity ( ABO ), and one showed significant sex heterogeneity ( ALDH2 ). The ALDH2 association was male specific (males p = 1.67e-24, females p = 0.126) and was additionally observed only in the East Asian ancestry (male) samples. These findings emphasize the need for more diverse datasets with large sample sizes to further understand the genetic predisposition of stroke in different ancestry and sex groups., Competing Interests: N.R.S. is an advisor for Abbott, Philips, and Shockwave and has received honoraria for speaking from Zoll, Cordis. C.J.W.’s spouse works at Regeneron Pharmaceuticals., (© 2023 The Authors.)

Published
2023
Full Text
View/download PDF

22. Author Correction: The power of genetic diversity in genome-wide association studies of lipids.

Author

Graham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, Surakka I, Ntalla I, Vedantam S, Winkler TW, Locke AE, Marouli E, Hwang MY, Han S, Narita A, Choudhury A, Bentley AR, Ekoru K, Verma A, Trivedi B, Martin HC, Hunt KA, Hui Q, Klarin D, Zhu X, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Ruotsalainen SE, Havulinna AS, Veturi Y, Feng Q, Rosenthal EA, Lingren T, Pacheco JA, Pendergrass SA, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Hindy G, Rasheed A, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Luan J, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Willemsen G, Wood AR, Ji Y, Gao Z, Haworth S, Mitchell RE, Chai JF, Aadahl M, Yao J, Manichaikul A, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Sidore C, Fiorillo E, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Thuesen BH, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Lamina C, Forer L, Scholz M, Galesloot TE, Bradfield JP, Daw EW, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Feitosa MF, Wojczynski MK, Preuss M, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Kember RL, Slieker RC, Lo KS, Zilhao NR, Le P, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Leonard HL, Marten J, Schmidt B, Arendt M, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Ahmed M, Jackson AU, Yousri NA, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Chai X, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Hung YJ, Chen S, Liu F, Yang J, Kentistou KA, Gorski M, Brumat M, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Xue C, Zhang J, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, Lee J, van der Laan SW, Chitrala KN, Weiss S, Zimmermann ME, Lee JY, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hildalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, Li X, Schwander K, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Highland HM, Young KL, Kawaguchi T, Thiery J, Bis JC, Nadkarni GN, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, Bhatti KF, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Chen YE, Bandinelli S, Dedoussis G, Thanaraj TA, Kardia SLR, Kato N, Schulze MB, Girotto G, Jung B, Böger CA, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, den Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Hunt SC, Walker M, Koistinen HA, Chandak GR, Yajnik CS, Mercader JM, Tusié-Luna T, Aguilar-Salinas CA, Villalpando CG, Orozco L, Fornage M, Tai ES, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Lu F, Qu J, Hishigaki H, Lin X, März W, Parra EJ, Cruz M, Gudnason V, Tardif JC, Lettre G, 't Hart LM, Elders PJM, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Psaty BM, Brandslund I, Pramstaller PP, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney LALM, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Cucca F, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, de Geus EJC, Cupples LA, van Meurs JBJ, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Justice AE, Baras A, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Thorsteinsdottir U, Stefansson K, Ho YL, Lynch JA, Rader DJ, Tsao PS, Chang KM, Cho K, O'Donnell CJ, Gaziano JM, Wilson P, Rotimi CN, Hazelhurst S, Ramsay M, Trembath RC, van Heel DA, Tamiya G, Yamamoto M, Kim BJ, Mohlke KL, Frayling TM, Hirschhorn JN, Kathiresan S, Boehnke M, Natarajan P, Peloso GM, Brown CD, Morris AP, Assimes TL, Deloukas P, Sun YV, and Willer CJ

Published
2023
Full Text
View/download PDF

23. Translating genetic association of lipid levels for biological and clinical application.

Author

Crone B, Krause AM, Hornsby WE, Willer CJ, and Surakka I

Subjects
Apolipoprotein B-100 genetics, Dyslipidemias ethnology, Genome-Wide Association Study, Humans, Hyperlipidemia, Familial Combined genetics, Proprotein Convertase 9 genetics, Receptors, LDL genetics, Risk Factors, Transcriptome, Exome Sequencing methods, Dyslipidemias genetics, Genetic Predisposition to Disease, Lipid Metabolism genetics
Abstract

Purpose of Review: This review focuses on the foundational evidence from the last two decades of lipid genetics research and describes the current status of data-driven approaches for transethnic GWAS, fine-mapping, transcriptome informed fine-mapping, and disease prediction., Recent Findings: Current lipid genetics research aims to understand the association mechanisms and clinical relevance of lipid loci as well as to capture population specific associations found in global ancestries. Recent genome-wide trans-ethnic association meta-analyses have identified 118 novel lipid loci reaching genome-wide significance. Gene-based burden tests of whole exome sequencing data have identified three genes-PCSK9, LDLR, and APOB-with significant rare variant burden associated with familial dyslipidemia. Transcriptome-wide association studies discovered five previously unreported lipid-associated loci. Additionally, the predictive power of genome-wide genetic risk scores amalgamating the polygenic determinants of lipid levels can potentially be used to increase the accuracy of coronary artery disease prediction., Conclusions: Lipids are one of the most successful group of traits in the era of genome-wide genetic discovery for identification of novel loci and plausible drug targets. However, a substantial fraction of lipid trait heritability remains unexplained. Further analysis of diverse ancestries and state of the art methods for association locus refinement could potentially reveal some of this missing heritability and increase the clinical application of the genomic association results.

Published
2021
Full Text
View/download PDF

24. High-resolution population-specific recombination rates and their effect on phasing and genotype imputation.

Author

Hassan S, Surakka I, Taskinen MR, Salomaa V, Palotie A, Wessman M, Tukiainen T, Pirinen M, Palta P, and Ripatti S

Subjects
Algorithms, Finland, Genotyping Techniques methods, Humans, Migraine Disorders genetics, Genome-Wide Association Study methods, Genotype, Haplotypes, Population genetics, Recombination, Genetic
Abstract

Previous research has shown that using population-specific reference panels has a significant effect on downstream population genomic analyses like haplotype phasing, genotype imputation, and association, especially in the context of population isolates. Here, we developed a high-resolution recombination rate mapping at 10 and 50 kb scale using high-coverage (20-30×) whole-genome sequenced data of 55 family trios from Finland and compared it to recombination rates of non-Finnish Europeans (NFE). We tested the downstream effects of the population-specific recombination rates in statistical phasing and genotype imputation in Finns as compared to the same analyses performed by using the NFE-based recombination rates. We found that Finnish recombination rates have a moderately high correlation (Spearman's ρ = 0.67-0.79) with NFE, although on average (across all autosomal chromosomes), Finnish rates (2.268 ± 0.4209 cM/Mb) are 12-14% lower than NFE (2.641 ± 0.5032 cM/Mb). Finnish recombination map was found to have no significant effect in haplotype phasing accuracy (switch error rates ~2%) and average imputation concordance rates (97-98% for common, 92-96% for low frequency and 78-90% for rare variants). Our results suggest that haplotype phasing and genotype imputation mostly depend on population-specific contexts like appropriate reference panels and their sample size, but not on population-specific recombination maps. Even though recombination rate estimates had some differences between the Finnish and NFE populations, haplotyping and imputation had not been noticeably affected by the recombination map used. Therefore, the currently available HapMap recombination maps seem robust for population-specific phasing and imputation pipelines, even in the context of relatively isolated populations like Finland.

Published
2021
Full Text
View/download PDF

25. Genetic predisposition may not improve prediction of cardiac surgery-associated acute kidney injury.

Author

Douville NJ, Larach DB, Lewis A, Bastarache L, Pandit A, He J, Heung M, Mathis M, Wanderer JP, Kheterpal S, Surakka I, and Kertai MD

Abstract

Background: The recent integration of genomic data with electronic health records has enabled large scale genomic studies on a variety of perioperative complications, yet genome-wide association studies on acute kidney injury have been limited in size or confounded by composite outcomes. Genome-wide association studies can be leveraged to create a polygenic risk score which can then be integrated with traditional clinical risk factors to better predict postoperative complications, like acute kidney injury. Methods: Using integrated genetic data from two academic biorepositories, we conduct a genome-wide association study on cardiac surgery-associated acute kidney injury. Next, we develop a polygenic risk score and test the predictive utility within regressions controlling for age, gender, principal components, preoperative serum creatinine, and a range of patient, clinical, and procedural risk factors. Finally, we estimate additive variant heritability using genetic mixed models. Results: Among 1,014 qualifying procedures at Vanderbilt University Medical Center and 478 at Michigan Medicine, 348 (34.3%) and 121 (25.3%) developed AKI, respectively. No variants exceeded genome-wide significance ( p < 5 × 10 -8 ) threshold, however, six previously unreported variants exceeded the suggestive threshold ( p < 1 × 10 -6 ). Notable variants detected include: 1) rs74637005, located in the exonic region of NFU1 and 2) rs17438465, located between EVX1 and HIBADH . We failed to replicate variants from prior unbiased studies of post-surgical acute kidney injury. Polygenic risk was not significantly associated with post-surgical acute kidney injury in any of the models, however, case duration (aOR = 1.002, 95% CI 1.000-1.003, p = 0.013), diabetes mellitus (aOR = 2.025, 95% CI 1.320-3.103, p = 0.001), and valvular disease (aOR = 0.558, 95% CI 0.372-0.835, p = 0.005) were significant in the full model. Conclusion: Polygenic risk score was not significantly associated with cardiac surgery-associated acute kidney injury and acute kidney injury may have a low heritability in this population. These results suggest that susceptibility is only minimally influenced by baseline genetic predisposition and that clinical risk factors, some of which are modifiable, may play a more influential role in predicting this complication. The overall impact of genetics in overall risk for cardiac surgery-associated acute kidney injury may be small compared to clinical risk factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Douville, Larach, Lewis, Bastarache, Pandit, He, Heung, Mathis, Wanderer, Kheterpal, Surakka and Kertai.)

Published
2023
Full Text
View/download PDF

26. Genetic variants in HFE are associated with non-alcoholic fatty liver disease in lean individuals.

Author

Sun Z, Pan X, Tian A, Surakka I, Wang T, Jiao X, He S, Song J, Tian X, Tong D, Wen J, Zhang Y, Liu W, and Chen P

Abstract

Background & Aims: Around 20% of patients with non-alcoholic fatty liver disease (NAFLD) are lean. Increasing evidence suggests that lean NAFLD is a unique subtype of the disease. We aimed to explore the metabolic profile, genetic basis, causal risk factors, and clinical sequelae underlying lean NAFLD., Methods: NAFLD was diagnosed by whole liver proton density fat fraction ≥5%. Whole liver proton density fat fraction and hepatic iron were quantified using magnetic resonance imaging in the UK Biobank. Individuals in this study were stratified according to the World Health Organization criteria of obesity, into lean, overweight, and obese. Mediation analysis, Mendelian randomisation analysis, and Bayesian networks were used to identify a risk factor or a clinical sequela of lean/obese NAFLD., Results: Lean NAFLD manifested a distinct metabolic profile, featured by elevated hepatic iron and fasting glucose. Four loci, namely, HFE rs1800562, SLC17A3-SLC17A2-TRIM38 rs9348697, PNPLA3 rs738409, and TM6SF2 rs58542926, were associated with lean NAFLD ( p <5 × 10 -8 ). HFE rs1800562 was specifically associated with lean NAFLD and demonstrated a significant mediation effect through elevating hepatic iron. Type 2 diabetes was the most pronounced clinical sequela of lean NAFLD, followed by liver cirrhosis., Conclusions: Our study suggested that HFE plays a potential steatogenic role rather than regulating iron homoeostasis in patients with lean NAFLD. The increased liver iron deposition is associated with lean NAFLD, whereas obese NAFLD is not related to hepatic iron. The clinical management of patients with lean NAFLD shall be concerned with the prevention and treatment of type 2 diabetes and liver cirrhosis., Impact and Implications: Lean NAFLD has a distinct natural history from obese NAFLD. This study underscored liver iron content and the genetic variant of the iron homoeostasis gene HFE as major risks of lean NAFLD, in addition to the unique metabolic profile. The development of type 2 diabetes or liver cirrhosis shall be closely monitored and prevented in patients with lean NAFLD., Competing Interests: The authors declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Published
2023
Full Text
View/download PDF

27. Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Author

van Leeuwen, E., Sabo, A., Bis, J., Huffman, J., Manichaikul, A., Smith, A., Feitosa, M., Demissie, S., Joshi, P., Duan, Q., Marten, J., van Klinken, J., Surakka, I., Nolte, I., Zhang, W., Mbarek, H., Li-Gao, R., Trompet, S., Verweij, N., Evangelou, E., Lyytikainen, L., Tayo, B., Deelen, J., van der Most, P., van der Laan, S., Arking, D., Morrison, A., Dehghan, A., Franco, O., Hofman, A., Rivadeneira, F., Sijbrands, E., Uitterlinden, A., Mychaleckyj, J., Campbell, A., Hocking, L., Padmanabhan, S., Brody, J., Rice, K., White, C., Harris, T., Isaacs, A., Campbell, H., Lange, L., Rudan, I., Kolcic, I., Navarro, P., Zemunik, T., Salomaa, V., LifeLines Cohort, S., Kooner, A., Kooner, J., Lehne, B., Scott, W., Tan, S., de Geus, E., Milaneschi, Y., Penninx, B., Willemsen, G., de Mutsert, R., Ford, I., Gansevoort, R., Segura-Lepe, M., Raitakari, O., Viikari, J., Nikus, K., Forrester, T., McKenzie, C., de Craen, A., de Ruijter, H., Group, C., Pasterkamp, G., Snieder, H., Oldehinkel, A., Slagboom, P., Cooper, R., Kahonen, M., Lehtimaki, T., Elliott, P., van der Harst, P., Jukema, J., Mook-Kanamori, D., Boomsma, D., Chambers, J., Swertz, M., Ripatti, S., Willems van Dijk, K., Vitart, V., Polasek, O., Hayward, C., Wilson, J., Gudnason, V., Rich, S., Psaty, B., Borecki, I., Boerwinkle, E., Rotter, J., Cupples, L., van Duijn, C., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, Biochemie, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Clinicum, Department of Public Health, Biostatistics Helsinki, Complex Disease Genetics, Psychiatry, EMGO - Mental health, Amsterdam Neuroscience - Complex Trait Genetics, EMGO+ - Quality of Care, Biological Psychology, Nanomedicine & Drug Targeting, Life Course Epidemiology (LCE), Isotope Research, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Epidemiology, and Internal Medicine

Subjects
Male, 0301 basic medicine, Netherlands Twin Register (NTR), Epidemiology, Genome-wide association study, DISEASE, GLUCOSE, Genotype, Genome-wide, TRANSCRIPTION, Genetics (clinical), GENE-EXPRESSION, Genetics & Heredity, Genetics, CHREBP, 1184 Genetics, developmental biology, physiology, Exons, Fasting, 11 Medical And Health Sciences, Middle Aged, LIPID-SYNTHESIS, 3142 Public health care science, environmental and occupational health, circulating lipid levels, Female, TRIGLYCERIDES, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Journal Article, Angiopoietin-Like Protein 4, Humans, 1000 Genomes Project, Gene, Genetic association, SREBP-1C, Genome, Human, MUTATIONS, Lipid metabolism, Complex traits, 06 Biological Sciences, ELEMENT-BINDING PROTEIN, 030104 developmental biology, Human genome, triglycerides, genetic, association, Angiopoietins, Genome-Wide Studies, Imputation (genetics), Genome-Wide Association Study, LifeLines Cohort Study
Abstract

So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ?60?000 individuals in the discovery stage and ?90?000 samples in the replication stage.Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Published
2016

28. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S.E., Clarke, S.L., Wu, K.H., Kanoni, S., Zajac, G.J.M., Ramdas, S., Surakka, I., Ntalla, I., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Hwang, M.Y., Han, S., Narita, A., Choudhury, A., Bentley, A.R., Ekoru, K., Verma, A., Trivedi, B., Martin, H.C., Hunt, K.A., Hui, Q., Klarin, D., Zhu, X, Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W., Brumpton, B.M., Rasheed, H., Ruotsalainen, S.E., Havulinna, A.S., Veturi, Y., Feng, Q., Rosenthal, E.A., Lingren, T., Pacheco, J.A., Pendergrass, S.A., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Hindy, G., Rasheed, A., Faul, J.D., Zhao, W., Weir, D.R., Turman, C., Huang, H., Graff, M, Mahajan, A., Brown, M.R., Zhang, W., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J., Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Willemsen, G., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Yao, J., Manichaikul, A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Sidore, C., Fiorillo, E., McDaid, A.F., Marques-Vidal, P., Wielscher, M., Trompet, S., Sattar, N., Galesloot, T.E., Kiemeney, B., Graaf, J. de, Lores de Motta, L., Pauper, M., Hollander, A.I. den, Sun, Y.V., Willer, C.J., Graham, S.E., Clarke, S.L., Wu, K.H., Kanoni, S., Zajac, G.J.M., Ramdas, S., Surakka, I., Ntalla, I., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Hwang, M.Y., Han, S., Narita, A., Choudhury, A., Bentley, A.R., Ekoru, K., Verma, A., Trivedi, B., Martin, H.C., Hunt, K.A., Hui, Q., Klarin, D., Zhu, X, Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W., Brumpton, B.M., Rasheed, H., Ruotsalainen, S.E., Havulinna, A.S., Veturi, Y., Feng, Q., Rosenthal, E.A., Lingren, T., Pacheco, J.A., Pendergrass, S.A., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Hindy, G., Rasheed, A., Faul, J.D., Zhao, W., Weir, D.R., Turman, C., Huang, H., Graff, M, Mahajan, A., Brown, M.R., Zhang, W., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J., Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Willemsen, G., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Yao, J., Manichaikul, A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Sidore, C., Fiorillo, E., McDaid, A.F., Marques-Vidal, P., Wielscher, M., Trompet, S., Sattar, N., Galesloot, T.E., Kiemeney, B., Graaf, J. de, Lores de Motta, L., Pauper, M., Hollander, A.I. den, Sun, Y.V., and Willer, C.J.

Abstract

Item does not contain fulltext, Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use(1). Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels(2), heart disease remains the leading cause of death worldwide(3). Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS(4-23) have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns(24). Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine(25), we anticipate that increased diversity of participants will lead to more accurate and equitable(26) application of polygenic scores in clinical practice.

Published
2021

29. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), Willer, C. J. (Cristen J.), Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), and Willer, C. J. (Cristen J.)

Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4‐23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Published
2021

30. The power of genetic diversity in genome-wide association studies of lipids.

Author

Graham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, Surakka I, Ntalla I, Vedantam S, Winkler TW, Locke AE, Marouli E, Hwang MY, Han S, Narita A, Choudhury A, Bentley AR, Ekoru K, Verma A, Trivedi B, Martin HC, Hunt KA, Hui Q, Klarin D, Zhu X, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Ruotsalainen SE, Havulinna AS, Veturi Y, Feng Q, Rosenthal EA, Lingren T, Pacheco JA, Pendergrass SA, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Hindy G, Rasheed A, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Luan J, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Willemsen G, Wood AR, Ji Y, Gao Z, Haworth S, Mitchell RE, Chai JF, Aadahl M, Yao J, Manichaikul A, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Sidore C, Fiorillo E, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Thuesen BH, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Lamina C, Forer L, Scholz M, Galesloot TE, Bradfield JP, Daw EW, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Feitosa MF, Wojczynski MK, Preuss M, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Kember RL, Slieker RC, Lo KS, Zilhao NR, Le P, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Leonard HL, Marten J, Schmidt B, Arendt M, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Ahmed M, Jackson AU, Yousri NA, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Chai X, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Hung YJ, Chen S, Liu F, Yang J, Kentistou KA, Gorski M, Brumat M, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Xue C, Zhang J, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, Lee J, van der Laan SW, Chitrala KN, Weiss S, Zimmermann ME, Lee JY, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hildalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, Li X, Schwander K, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Highland HM, Young KL, Kawaguchi T, Thiery J, Bis JC, Nadkarni GN, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, Bhatti KF, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Chen YE, Bandinelli S, Dedoussis G, Thanaraj TA, Kardia SLR, Kato N, Schulze MB, Girotto G, Jung B, Böger CA, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, den Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Hunt SC, Walker M, Koistinen HA, Chandak GR, Yajnik CS, Mercader JM, Tusié-Luna T, Aguilar-Salinas CA, Villalpando CG, Orozco L, Fornage M, Tai ES, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Lu F, Qu J, Hishigaki H, Lin X, März W, Parra EJ, Cruz M, Gudnason V, Tardif JC, Lettre G, 't Hart LM, Elders PJM, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Psaty BM, Brandslund I, Pramstaller PP, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney LALM, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Cucca F, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, de Geus EJC, Cupples LA, van Meurs JBJ, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Justice AE, Baras A, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Thorsteinsdottir U, Stefansson K, Ho YL, Lynch JA, Rader DJ, Tsao PS, Chang KM, Cho K, O'Donnell CJ, Gaziano JM, Wilson P, Rotimi CN, Hazelhurst S, Ramsay M, Trembath RC, van Heel DA, Tamiya G, Yamamoto M, Kim BJ, Mohlke KL, Frayling TM, Hirschhorn JN, Kathiresan S, Boehnke M, Natarajan P, Peloso GM, Brown CD, Morris AP, Assimes TL, Deloukas P, Sun YV, and Willer CJ

Subjects
Genetic Predisposition to Disease genetics, Humans, Linkage Disequilibrium, Multifactorial Inheritance, Polymorphism, Single Nucleotide genetics, Population Groups, Cardiovascular Diseases genetics, Genome-Wide Association Study methods
Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , heart disease remains the leading cause of death worldwide 3 . Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS 4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns 24 . Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine 25 , we anticipate that increased diversity of participants will lead to more accurate and equitable 26 application of polygenic scores in clinical practice., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2021
Full Text
View/download PDF

31. Sex-Specific Survival Bias and Interaction Modeling in Coronary Artery Disease Risk Prediction.

Author

Surakka I, Wolford BN, Ritchie SC, Hornsby WE, Sutton NR, Elvenstad Gabrielsen M, Skogholt AH, Thomas L, Inouye M, Hveem K, and Willer CJ

Subjects
Male, Female, Humans, Risk Assessment, Risk Factors, Sex Factors, Coronary Artery Disease epidemiology, Coronary Artery Disease genetics, Coronary Artery Disease diagnosis, Cardiovascular Diseases
Abstract

Background: The 10-year Atherosclerotic Cardiovascular Disease risk score is the standard approach to predict risk of incident cardiovascular events, and recently, addition of coronary artery disease (CAD) polygenic scores has been evaluated. Although age and sex strongly predict the risk of CAD, their interaction with genetic risk prediction has not been systematically examined. This study performed an extensive evaluation of age and sex effects in genetic CAD risk prediction., Methods: The population-based Norwegian HUNT2 (Trøndelag Health Study 2) cohort of 51 036 individuals was used as the primary dataset. Findings were replicated in the UK Biobank (372 410 individuals). Models for 10-year CAD risk were fitted using Cox proportional hazards, and Harrell concordance index, sensitivity, and specificity were compared., Results: Inclusion of age and sex interactions of CAD polygenic score to the prediction models increased the C-index and sensitivity by accounting for nonadditive effects of CAD polygenic score and likely countering the observed survival bias in the baseline. The sensitivity for females was lower than males in all models including genetic information. We identified a total of 82.6% of incident CAD cases by using a 2-step approach: (1) Atherosclerotic Cardiovascular Disease risk score (74.1%) and (2) the CAD polygenic score interaction model for those in low clinical risk (additional 8.5%)., Conclusions: These findings highlight the importance and complexity of genetic risk in predicting CAD. There is a need for modeling age- and sex-interaction terms with polygenic scores to optimize detection of individuals at high risk, those who warrant preventive interventions. Sex-specific studies are needed to understand and estimate CAD risk with genetic information.

Published
2023
Full Text
View/download PDF

32. Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts.

Author

Wang Y, Namba S, Lopera E, Kerminen S, Tsuo K, Läll K, Kanai M, Zhou W, Wu KH, Favé MJ, Bhatta L, Awadalla P, Brumpton B, Deelen P, Hveem K, Lo Faro V, Mägi R, Murakami Y, Sanna S, Smoller JW, Uzunovic J, Wolford BN, Willer C, Gamazon ER, Cox NJ, Surakka I, Okada Y, Martin AR, and Hirbo J

Abstract

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era., Competing Interests: E.R.G. received an honorarium from the journal Circulation Research of the American Heart Association as a member of the editorial board., (© 2022 The Author(s).)

Published
2023
Full Text
View/download PDF

33. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

Author

Zhou, W. (Wei), Brumpton, B. (Ben), Kabil, O. (Omer), Gudmundsson, J. (Julius), Thorleifsson, G. (Gudmar), Weinstock, J. (Josh), Zawistowski, M. (Matthew), Nielsen, J.B. (Jonas B.), Chaker, L. (Layal), Medici, M. (Marco), Teumer, A. (Alexander), Naitza, S. (Silvia), Sanna, S. (Serena), Schultheiss, U.T. (Ulla T.), Cappola, A.R. (Anne), Karjalainen, J. (Juha), Kurki, M. (Mitja), Oneka, M. (Morgan), Taylor, P.N. (Peter N.), Fritsche, L.G. (Lars), Graham, S.E. (Sarah E.), Wolford, B.N. (Brooke N.), Overton, W. (William), Rasheed, H. (Humaira), Haug, E.B. (Eirin B.), Gabrielsen, M.E. (Maiken Elvestad), Skogholt, A.H. (Anne Heidi), Surakka, I. (Ida), Davey Smith, G. (George), Pandit, A. (Anita), Roychowdhury, T. (Tanmoy), Hornsby, W.E. (Whitney E.), Jonasson, J.G. (Jon G.), Senter, L. (Leigha), Liyanarachchi, S. (Sandya), Ringel, M.D. (Matthew D.), Xu, L. (Li), Kiemeney, L.A. (Lambertus A.), He, H. (Hao), Netea-Maier, R.T. (Romana), Mayordomo, J.I. (José), Plantinga, T.S. (Theo S.), Hrafnkelsson, J. (Jon), Hjartarson, H. (Hannes), Sturgis, E.M. (Erich M.), Palotie, A. (Aarno), Daly, M.J. (Mark), Citterio, C.E. (Cintia E.), Arvan, P. (Peter), Brummett, C.M. (Chad M.), Boehnke, M. (Michael), La Chapelle, A. (Albert) de, Stefansson, K. (Kari), Hveem, K. (Kristian), Willer, C.J. (Cristen), Asvold, B.O. (Bjorn O.), Zhou, W. (Wei), Brumpton, B. (Ben), Kabil, O. (Omer), Gudmundsson, J. (Julius), Thorleifsson, G. (Gudmar), Weinstock, J. (Josh), Zawistowski, M. (Matthew), Nielsen, J.B. (Jonas B.), Chaker, L. (Layal), Medici, M. (Marco), Teumer, A. (Alexander), Naitza, S. (Silvia), Sanna, S. (Serena), Schultheiss, U.T. (Ulla T.), Cappola, A.R. (Anne), Karjalainen, J. (Juha), Kurki, M. (Mitja), Oneka, M. (Morgan), Taylor, P.N. (Peter N.), Fritsche, L.G. (Lars), Graham, S.E. (Sarah E.), Wolford, B.N. (Brooke N.), Overton, W. (William), Rasheed, H. (Humaira), Haug, E.B. (Eirin B.), Gabrielsen, M.E. (Maiken Elvestad), Skogholt, A.H. (Anne Heidi), Surakka, I. (Ida), Davey Smith, G. (George), Pandit, A. (Anita), Roychowdhury, T. (Tanmoy), Hornsby, W.E. (Whitney E.), Jonasson, J.G. (Jon G.), Senter, L. (Leigha), Liyanarachchi, S. (Sandya), Ringel, M.D. (Matthew D.), Xu, L. (Li), Kiemeney, L.A. (Lambertus A.), He, H. (Hao), Netea-Maier, R.T. (Romana), Mayordomo, J.I. (José), Plantinga, T.S. (Theo S.), Hrafnkelsson, J. (Jon), Hjartarson, H. (Hannes), Sturgis, E.M. (Erich M.), Palotie, A. (Aarno), Daly, M.J. (Mark), Citterio, C.E. (Cintia E.), Arvan, P. (Peter), Brummett, C.M. (Chad M.), Boehnke, M. (Michael), La Chapelle, A. (Albert) de, Stefansson, K. (Kari), Hveem, K. (Kristian), Willer, C.J. (Cristen), and Asvold, B.O. (Bjorn O.)

Abstract

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.

Published
2020
Full Text
View/download PDF

34. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author

Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), Codd, V. (Veryan), Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), and Codd, V. (Veryan)

Abstract

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Published
2020
Full Text
View/download PDF

35. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author

Li, C, Stoma, S, Lotta, LA, Warner, S, Albrecht, E, Allione, A, Arp, PP, Broer, L, Buxton, JL, Alves, ADSC, Deelen, J, Fedko, IO, Gordon, SD, Jiang, T, Karlsson, R, Kerrison, N, Loe, TK, Mangino, M, Milaneschi, Y, Miraglio, B, Pervjakova, N, Russo, A, Surakka, I, van der Spek, A, Verhoeven, JE, Amin, N, Beekman, M, Blakemore, A, Canzian, F, Hamby, SE, Hottenga, J-J, Jones, PD, Jousilahti, P, Magi, R, Medland, SE, Montgomery, GW, Nyholt, DR, Perola, M, Pietilainen, KH, Salomaa, V, Sillanpaa, E, Suchiman, HE, van Heemst, D, Willemsen, G, Agudo, A, Boeing, H, Boomsma, D, Chirlaque, M-D, Fagherazzi, G, Ferrari, P, Franks, P, Gieger, C, Eriksson, JG, Gunter, M, Hagg, S, Hovatta, I, Imaz, L, Kaprio, J, Kaaks, R, Key, T, Krogh, V, Martin, NG, Melander, O, Metspalu, A, Moreno, C, Onland-Moret, NC, Nilsson, P, Ong, KK, Overvad, K, Palli, D, Panico, S, Pedersen, NL, Penninx, BWJH, Ramon Quiros, J, Riitta Jarvelin, M, Rodriguez-Barranco, M, Scott, RA, Severi, G, Slagboom, PE, Spector, TD, Tjonneland, A, Trichopoulou, A, Tumino, R, Uitterlinden, AG, van der Schouw, YT, van Duijn, CM, Weiderpass, E, Denchi, EL, Matullo, G, Butterworth, AS, Danesh, J, Samani, NJ, Wareham, NJ, Nelson, CP, Langenberg, C, Codd, V, Li, C, Stoma, S, Lotta, LA, Warner, S, Albrecht, E, Allione, A, Arp, PP, Broer, L, Buxton, JL, Alves, ADSC, Deelen, J, Fedko, IO, Gordon, SD, Jiang, T, Karlsson, R, Kerrison, N, Loe, TK, Mangino, M, Milaneschi, Y, Miraglio, B, Pervjakova, N, Russo, A, Surakka, I, van der Spek, A, Verhoeven, JE, Amin, N, Beekman, M, Blakemore, A, Canzian, F, Hamby, SE, Hottenga, J-J, Jones, PD, Jousilahti, P, Magi, R, Medland, SE, Montgomery, GW, Nyholt, DR, Perola, M, Pietilainen, KH, Salomaa, V, Sillanpaa, E, Suchiman, HE, van Heemst, D, Willemsen, G, Agudo, A, Boeing, H, Boomsma, D, Chirlaque, M-D, Fagherazzi, G, Ferrari, P, Franks, P, Gieger, C, Eriksson, JG, Gunter, M, Hagg, S, Hovatta, I, Imaz, L, Kaprio, J, Kaaks, R, Key, T, Krogh, V, Martin, NG, Melander, O, Metspalu, A, Moreno, C, Onland-Moret, NC, Nilsson, P, Ong, KK, Overvad, K, Palli, D, Panico, S, Pedersen, NL, Penninx, BWJH, Ramon Quiros, J, Riitta Jarvelin, M, Rodriguez-Barranco, M, Scott, RA, Severi, G, Slagboom, PE, Spector, TD, Tjonneland, A, Trichopoulou, A, Tumino, R, Uitterlinden, AG, van der Schouw, YT, van Duijn, CM, Weiderpass, E, Denchi, EL, Matullo, G, Butterworth, AS, Danesh, J, Samani, NJ, Wareham, NJ, Nelson, CP, Langenberg, C, and Codd, V

Abstract

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Published
2020

36. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

Author

Kanoni S, Graham SE, Wang Y, Surakka I, Ramdas S, Zhu X, Clarke SL, Bhatti KF, Vedantam S, Winkler TW, Locke AE, Marouli E, Zajac GJM, Wu KH, Ntalla I, Hui Q, Klarin D, Hilliard AT, Wang Z, Xue C, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Hwang MY, Han S, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Havulinna AS, Veturi Y, Pacheco JA, Rosenthal EA, Lingren T, Feng Q, Kullo IJ, Narita A, Takayama J, Martin HC, Hunt KA, Trivedi B, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Rasheed A, Hindy G, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Choudhury A, Sengupta D, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Luan J, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Wood AR, Ji Y, Gao Z, Haworth S, Yousri NA, Mitchell RE, Chai JF, Aadahl M, Bjerregaard AA, Yao J, Manichaikul A, Hwu CM, Hung YJ, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Mauro P, Matteo F, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Lamina C, Forer L, Scholz M, Galesloot TE, Bradfield JP, Ruotsalainen SE, Daw E, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Vazquez-Moreno M, Feitosa MF, Wojczynski MK, Wang Z, Preuss MH, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Tsao NL, Verma A, Slieker RC, Lo KS, Zilhao NR, Le P, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Demirkan A, Leonard HL, Marten J, Frank M, Schmidt B, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Nongmaithem SS, Bayyana S, Stringham HM, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Chen S, Liu F, Yang J, Kentistou KA, Banas B, Nardone GG, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, van der Laan SW, Chitrala KN, Weiss S, Bentley AR, Doumatey AP, Adeyemo AA, Lee JY, Petersen ERB, Nielsen AA, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hidalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, Li X, Liang J, Tang H, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Kawaguchi T, Thiery J, Bis JC, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Zimmermann ME, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Bandinelli S, Dedoussis G, Thanaraj TA, Kardia SLR, Peyser PA, Kato N, Schulze MB, Girotto G, Böger CA, Jung B, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Tusié-Luna T, Aguilar-Salinas CA, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Hunt SC, Walker M, Koistinen HA, Chandak GR, Mercader JM, Costanzo MC, Jang D, Burtt NP, Villalpando CG, Orozco L, Fornage M, Tai E, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Jin ZB, Qu J, Hishigaki H, Lin X, März W, Gudnason V, Tardif JC, Lettre G, Hart LM', Elders PJM, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Parra EJ, Cruz M, Psaty BM, Brandslund I, Pramstaller PP, Rotimi CN, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney LALM, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Francesco C, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Chuang LM, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Li H, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, Willemsen AHM, Cupples L, van Meurs JBJ, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, Hazelhurst S, Ramsay M, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Baras A, Justice AE, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Tamiya G, Yamamoto M, van Heel DA, Trembath RC, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Kim BJ, Thorsteinsdottir U, Stefansson K, Zhang J, Chen Y, Ho YL, Lynch JA, Rader DJ, Tsao PS, Chang KM, Cho K, O'Donnell CJ, Gaziano JM, Wilson PWF, Frayling TM, Hirschhorn JN, Kathiresan S, Mohlke KL, Sun YV, Morris AP, Boehnke M, Brown CD, Natarajan P, Deloukas P, Willer CJ, Assimes TL, and Peloso GM

Subjects
Humans, Sex Characteristics, Phenotype, Lipids genetics, Polymorphism, Single Nucleotide, Genetic Pleiotropy, Genome-Wide Association Study, Genetic Predisposition to Disease
Abstract

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery., Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism., Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., (© 2022. The Author(s).)

Published
2022
Full Text
View/download PDF

37. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.

Author

Aragam KG, Jiang T, Goel A, Kanoni S, Wolford BN, Atri DS, Weeks EM, Wang M, Hindy G, Zhou W, Grace C, Roselli C, Marston NA, Kamanu FK, Surakka I, Venegas LM, Sherliker P, Koyama S, Ishigaki K, Åsvold BO, Brown MR, Brumpton B, de Vries PS, Giannakopoulou O, Giardoglou P, Gudbjartsson DF, Güldener U, Haider SMI, Helgadottir A, Ibrahim M, Kastrati A, Kessler T, Kyriakou T, Konopka T, Li L, Ma L, Meitinger T, Mucha S, Munz M, Murgia F, Nielsen JB, Nöthen MM, Pang S, Reinberger T, Schnitzler G, Smedley D, Thorleifsson G, von Scheidt M, Ulirsch JC, Arnar DO, Burtt NP, Costanzo MC, Flannick J, Ito K, Jang DK, Kamatani Y, Khera AV, Komuro I, Kullo IJ, Lotta LA, Nelson CP, Roberts R, Thorgeirsson G, Thorsteinsdottir U, Webb TR, Baras A, Björkegren JLM, Boerwinkle E, Dedoussis G, Holm H, Hveem K, Melander O, Morrison AC, Orho-Melander M, Rallidis LS, Ruusalepp A, Sabatine MS, Stefansson K, Zalloua P, Ellinor PT, Farrall M, Danesh J, Ruff CT, Finucane HK, Hopewell JC, Clarke R, Gupta RM, Erdmann J, Samani NJ, Schunkert H, Watkins H, Willer CJ, Deloukas P, Kathiresan S, and Butterworth AS

Subjects
Humans, Genome-Wide Association Study, Coronary Artery Disease genetics
Abstract

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD., (© 2022. The Author(s).)

Published
2022
Full Text
View/download PDF

38. Quality control and conduct of genome-wide association meta-analyses

Author

Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis GR, Absher D, Alavere H, Albrecht E, Allen HL, Almgren P, Amin N, Amouyel P, Anderson D, Arnold AM, Arveiler D, Aspelund T, Asselbergs FW, Assimes TL, Atalay M, Attwood AP, Atwood LD, Bakker SJ, Balkau B, Balmforth AJ, Barlassina C, Barroso I, Basart H, Bauer S, Beckmann JS, Beilby JP, Bennett AJ, Ben Shlomo Y, Bergman RN, Bergmann S, Berndt SI, Biffar R, Di Blasio AM, Boehm BO, Boehnke M, Boeing H, Boerwinkle E, Bolton JL, Bonnefond A, Bonnycastle LL, Boomsma DI, Borecki IB, Bornstein SR, Bouatia Naji N, Boucher G, Bragg Gresham JL, BRAMBILLA, PAOLO, Bruinenberg M, Buchanan TA, Buechler C, Cadby G, Campbell H, Caulfield MJ, Cavalcanti Proença C, CESANA, GIANCARLO, Chanock SJ, Chasman DI, Chen YD, Chines PS, Clegg DJ, Coin L, Collins FS, Connell JM, Cookson W, Cooper MN, Croteau Chonka DC, Cupples LA, Cusi D, Day FR, Day IN, Dedoussis GV, Dei M, Deloukas P, Dermitzakis ET, Dimas AS, Dimitriou M, Dixon AL, Dörr M, van Duijn CM, Ebrahim S, Edkins S, Eiriksdottir G, Eisinger K, Eklund N, Elliott P, Erbel R, Erdmann J, Erdos MR, Eriksson JG, Esko T, Estrada K, Evans DM, de Faire U, Fall T, Farrall M, Feitosa MF, Ferrario MM, Ferreira T, Ferrières J, Fischer K, Fisher E, Fowkes G, Fox CS, Franke L, Franks PW, Fraser RM, Frau F, Frayling T, Freimer NB, Froguel P, Fu M, Gaget S, Ganna A, Gejman PV, Gentilini D, Geus EJ, Gieger C, Gigante B, Gjesing AP, Glazer NL, Goddard ME, Goel A, Grallert H, Gräßler J, Grönberg H, Groop LC, Groves CJ, Gudnason V, Guiducci C, Gustafsson S, Gyllensten U, Hall AS, Hall P, Hallmans G, Hamsten A, Hansen T, Haritunians T, Harris TB, van der Harst P, Hartikainen AL, Hassanali N, Hattersley AT, Havulinna AS, Hayward C, Heard Costa NL, Heath AC, Hebebrand J, Heid IM, den Heijer M, Hengstenberg C, Herzig KH, Hicks AA, Hingorani A, Hinney A, Hirschhorn JN, Hofman A, Holmes CC, Homuth G, Hottenga JJ, Hovingh KG, Hu FB, Hu YJ, Huffman JE, Hui J, Huikuri H, Humphries SE, Hung J, Hunt SE, Hunter D, Hveem K, Hyppönen E, Igl W, Illig T, Ingelsson E, Iribarren C, Isomaa B, Jackson AU, Jacobs KB, James AL, Jansson JO, Jarick I, Jarvelin MR, Jöckel KH, Johansson Å, Johnson T, Jolley J, Jørgensen T, Jousilahti P, Jula A, Justice AE, Kaakinen M, Kähönen M, Kajantie E, Kanoni S, Kao WH, Kaplan LM, Kaplan RC, Kaprio J, Kapur K, Karpe F, Kathiresan S, Kee F, Keinanen Kiukaanniemi SM, Ketkar S, Kettunen J, Khaw KT, Kiemeney LA, Kilpeläinen TO, Kinnunen L, Kivimaki M, Kivmaki M, Van der Klauw MM, Kleber ME, Knowles JW, Koenig W, Kolcic I, Kolovou G, König IR, Koskinen S, Kovacs P, Kraft P, Kraja AT, Kristiansson K, KrjutÅjkov K, Kroemer HK, Krohn JP, Krzelj V, Kuh D, Kulzer JR, Kumari M, Kutalik Z, Kuulasmaa K, Kuusisto J, Kvaloy K, Laakso M, Laitinen JH, Lakka TA, Lamina C, Langenberg C, Lantieri O, Lathrop GM, Launer LJ, Lawlor DA, Lawrence RW, Leach IM, Lecoeur C, Lee SH, Lehtimäki T, Leitzmann MF, Lettre G, Levinson DF, Li G, Li S, Liang L, Lin DY, Lind L, Lindgren CM, Lindström J, Liu J, Liuzzi A, Locke AE, Lokki ML, Loley C, Loos RJ, Lorentzon M, Luan J, Luben RN, Ludwig B, Madden PA, Mägi R, Magnusson PK, Mangino M, Manunta P, Marek D, Marre M, Martin NG, März W, Maschio A, Mathieson I, McArdle WL, McCaroll SA, McCarthy A, McCarthy MI, McKnight B, Medina Gomez C, Medland SE, Meitinger T, Metspalu A, van Meurs JB, Meyre D, Midthjell K, Mihailov E, Milani L, Min JL, Moebus S, Moffatt MF, Mohlke KL, Molony C, Monda KL, Montgomery GW, Mooser V, Morken MA, Morris AD, Morris AP, Mühleisen TW, Müller Nurasyid M, Munroe PB, Musk AW, Narisu N, Navis G, Neale BM, Nelis M, Nemesh J, Neville MJ, Ngwa JS, Nicholson G, Nieminen MS, Njølstad I, Nohr EA, Nolte IM, North KE, Nöthen MM, Nyholt DR, O'Connell JR, Ohlsson C, Oldehinkel AJ, van Ommen GJ, Ong KK, Oostra BA, Ouwehand WH, Palmer CN, Palmer LJ, Palotie A, Paré G, Parker AN, Paternoster L, Pawitan Y, Pechlivanis S, Peden JF, Pedersen NL, Pedersen O, Pellikka N, Peltonen L, Penninx B, Perola M, Perry JR, Person T, Peters A, Peters MJ, Pichler I, Pietiläinen KH, Platou CG, Polasek O, Pouta A, Power C, Pramstaller PP, Preuss M, Price JF, Prokopenko I, Province MA, Psaty BM, Purcell S, Pütter C, Qi L, Quertermous T, Radhakrishnan A, Raitakari O, Randall JC, Rauramaa R, Rayner NW, Rehnberg E, Rendon A, Ridderstråle M, Ridker PM, Ripatti S, Rissanen A, Rivadeneira F, Rivolta C, Robertson NR, Rose LM, Rudan I, Saaristo TE, Sager H, Salomaa V, Samani NJ, Sambrook JG, Sanders AR, Sandholt C, Sanna S, Saramies J, Schadt EE, Scherag A, Schipf S, Schlessinger D, Schreiber S, Schunkert H, Schwarz PE, Scott LJ, Shi J, Shin SY, Shuldiner AR, Shungin D, Signorini S, Silander K, Sinisalo J, Skrobek B, Smit JH, Smith AV, Smith GD, Snieder H, Soranzo N, Sørensen TI, Sovio U, Spector TD, Speliotes EK, Stančáková A, Stark K, Stefansson K, Steinthorsdottir V, Stephens JC, Stirrups K, Stolk RP, Strachan DP, Strawbridge RJ, Stringham HM, Stumvoll M, Surakka I, Swift AJ, Syvanen AC, Tammesoo ML, Teder Laving M, Teslovich TM, Teumer A, Theodoraki EV, Thomson B, Thorand B, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tönjes A, Tregouet DA, Tremoli E, Trip MD, Tuomi T, Tuomilehto J, Tyrer J, Uda M, Uitterlinden AG, Usala G, Uusitupa M, Valle TT, Vandenput L, Vatin V, Vedantam S, de Vegt F, Vermeulen SH, Viikari J, Virtamo J, Visscher PM, Vitart V, Van Vliet Ostaptchouk JV, Voight BF, Vollenweider P, Volpato CB, Völzke H, Waeber G, Waite LL, Wallaschofski H, Walters GB, Wang Z, Wareham NJ, Watanabe RM, Watkins H, Weedon MN, Welch R, Weyant RJ, Wheeler E, White CC, Wichmann HE, Widen E, Wild SH, Willemsen G, Willer CJ, Wilsgaard T, Wilson JF, van Wingerden S, Winkelmann BR, Winkler TW, Witte DR, Witteman JC, Wolffenbuttel BH, Wong A, Wood AR, Workalemahu T, Wright AF, Yang J, Yarnell JW, Zgaga L, Zhao JH, Zillikens MC, Zitting P, Zondervan KT, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis, G, Absher, D, Alavere, H, Albrecht, E, Allen, H, Almgren, P, Amin, N, Amouyel, P, Anderson, D, Arnold, A, Arveiler, D, Aspelund, T, Asselbergs, F, Assimes, T, Atalay, M, Attwood, A, Atwood, L, Bakker, S, Balkau, B, Balmforth, A, Barlassina, C, Barroso, I, Basart, H, Bauer, S, Beckmann, J, Beilby, J, Bennett, A, Ben Shlomo, Y, Bergman, R, Bergmann, S, Berndt, S, Biffar, R, Di Blasio, A, Boehm, B, Boehnke, M, Boeing, H, Boerwinkle, E, Bolton, J, Bonnefond, A, Bonnycastle, L, Boomsma, D, Borecki, I, Bornstein, S, Bouatia Naji, N, Boucher, G, Bragg Gresham, J, Brambilla, P, Bruinenberg, M, Buchanan, T, Buechler, C, Cadby, G, Campbell, H, Caulfield, M, Cavalcanti Proença, C, Cesana, G, Chanock, S, Chasman, D, Chen, Y, Chines, P, Clegg, D, Coin, L, Collins, F, Connell, J, Cookson, W, Cooper, M, Cupples, L, Cusi, D, Day, I, Dedoussis, G, Dei, M, Deloukas, P, Dermitzakis, E, Dimas, A, Dimitriou, M, Dixon, A, Dörr, M, van Duijn, C, Ebrahim, S, Edkins, S, Eiriksdottir, G, Eisinger, K, Eklund, N, Elliott, P, Erbel, R, Erdmann, J, Erdos, M, Eriksson, J, Estrada, K, Evans, D, de Faire, U, Farrall, M, Feitosa, M, Ferrario, M, Ferrières, J, Fischer, K, Fisher, E, Fowkes, G, Fox, C, Franke, L, Franks, P, Fraser, R, Frau, F, Frayling, T, Freimer, N, Froguel, P, Fu, M, Gaget, S, Ganna, A, Gejman, P, Gentilini, D, Geus, E, Gieger, C, Gigante, B, Gjesing, A, Glazer, N, Goddard, M, Goel, A, Grallert, H, Gräßler, J, Grönberg, H, Groop, L, Groves, C, Gudnason, V, Guiducci, C, Gyllensten, U, Hall, A, Hall, P, Hallmans, G, Hamsten, A, Hansen, T, Haritunians, T, Harris, T, van der Harst, P, Hartikainen, A, Hassanali, N, Hattersley, A, Havulinna, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, den Heijer, M, Hengstenberg, C, Herzig, K, Hicks, A, Hingorani, A, Hinney, A, Hirschhorn, J, Hofman, A, Holmes, C, Homuth, G, Hottenga, J, Hovingh, K, Hu, F, Hu, Y, Huffman, J, Hui, J, Huikuri, H, Humphries, S, Hung, J, Hunt, S, Hunter, D, Hveem, K, Hyppönen, E, Igl, W, Illig, T, Ingelsson, E, Iribarren, C, Isomaa, B, Jackson, A, Jacobs, K, James, A, Jansson, J, Jarick, I, Jarvelin, M, Jöckel, K, Johansson, Å, Johnson, T, Jolley, J, Jørgensen, T, Jousilahti, P, Jula, A, Kaakinen, M, Kähönen, M, Kajantie, E, Kanoni, S, Kao, W, Kaplan, L, Kaplan, R, Kaprio, J, Kapur, K, Karpe, F, Kathiresan, S, Kee, F, Keinanen Kiukaanniemi, S, Ketkar, S, Kettunen, J, Khaw, K, Kiemeney, L, Kinnunen, L, Kivimaki, M, Kivmaki, M, Van der Klauw, M, Kleber, M, Knowles, J, Koenig, W, Kolcic, I, Kolovou, G, König, I, Koskinen, S, Kovacs, P, Kraft, P, Kraja, A, Kristiansson, K, Krjutåjkov, K, Kroemer, H, Krohn, J, Krzelj, V, Kuh, D, Kulzer, J, Kumari, M, Kuulasmaa, K, Kuusisto, J, Kvaloy, K, Laakso, M, Laitinen, J, Lakka, T, Lamina, C, Langenberg, C, Lantieri, O, Lathrop, G, Launer, L, Lawlor, D, Lawrence, R, Leach, I, Lecoeur, C, Lee, S, Lehtimäki, T, Leitzmann, M, Lettre, G, Levinson, D, Li, G, Li, S, Liang, L, Lin, D, Lind, L, Lindgren, C, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Loley, C, Lorentzon, M, Luben, R, Ludwig, B, Madden, P, Magnusson, P, Mangino, M, Manunta, P, Marek, D, Marre, M, Martin, N, März, W, Maschio, A, Mathieson, I, Mcardle, W, Mccaroll, S, Mccarthy, A, Mccarthy, M, Mcknight, B, Medina Gomez, C, Medland, S, Meitinger, T, Metspalu, A, van Meurs, J, Meyre, D, Midthjell, K, Mihailov, E, Milani, L, Min, J, Moebus, S, Moffatt, M, Mohlke, K, Molony, C, Monda, K, Montgomery, G, Mooser, V, Morken, M, Morris, A, Mühleisen, T, Müller Nurasyid, M, Munroe, P, Musk, A, Narisu, N, Navis, G, Neale, B, Nelis, M, Nemesh, J, Neville, M, Ngwa, J, Nicholson, G, Nieminen, M, Njølstad, I, Nohr, E, Nolte, I, North, K, Nöthen, M, Nyholt, D, O'Connell, J, Ohlsson, C, Oldehinkel, A, van Ommen, G, Ong, K, Oostra, B, Ouwehand, W, Palmer, C, Palmer, L, Palotie, A, Paré, G, Parker, A, Paternoster, L, Pawitan, Y, Pechlivanis, S, Peden, J, Pedersen, N, Pedersen, O, Pellikka, N, Peltonen, L, Penninx, B, Perola, M, Perry, J, Person, T, Peters, A, Peters, M, Pichler, I, Pietiläinen, K, Platou, C, Polasek, O, Pouta, A, Power, C, Pramstaller, P, Preuss, M, Price, J, Prokopenko, I, Province, M, Psaty, B, Purcell, S, Pütter, C, Qi, L, Quertermous, T, Radhakrishnan, A, Raitakari, O, Rauramaa, R, Rayner, N, Rehnberg, E, Rendon, A, Ridderstråle, M, Ridker, P, Ripatti, S, Rissanen, A, Rivadeneira, F, Rivolta, C, Robertson, N, Rose, L, Rudan, I, Saaristo, T, Sager, H, Salomaa, V, Samani, N, Sambrook, J, Sanders, A, Sandholt, C, Sanna, S, Saramies, J, Schadt, E, Schipf, S, Schlessinger, D, Schreiber, S, Schunkert, H, Schwarz, P, Scott, L, Shi, J, Shin, S, Shuldiner, A, Shungin, D, Signorini, S, Silander, K, Sinisalo, J, Skrobek, B, Smit, J, Smith, A, Smith, G, Snieder, H, Soranzo, N, Sørensen, T, Sovio, U, Spector, T, Speliotes, E, Stančáková, A, Stark, K, Stefansson, K, Steinthorsdottir, V, Stephens, J, Stirrups, K, Stolk, R, Strachan, D, Strawbridge, R, Stringham, H, Stumvoll, M, Surakka, I, Swift, A, Syvanen, A, Tammesoo, M, Teder Laving, M, Teslovich, T, Teumer, A, Theodoraki, E, Thomson, B, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Timpson, N, Tönjes, A, Tregouet, D, Tremoli, E, Trip, M, Tuomi, T, Tuomilehto, J, Tyrer, J, Uda, M, Uitterlinden, A, Usala, G, Uusitupa, M, Valle, T, Vandenput, L, Vatin, V, de Vegt, F, Vermeulen, S, Viikari, J, Virtamo, J, Visscher, P, Vitart, V, Van Vliet Ostaptchouk, J, Voight, B, Vollenweider, P, Volpato, C, Völzke, H, Waeber, G, Waite, L, Wallaschofski, H, Walters, G, Wang, Z, Wareham, N, Watanabe, R, Watkins, H, Weedon, M, Welch, R, Weyant, R, Wheeler, E, White, C, Wichmann, H, Widen, E, Wild, S, Willemsen, G, Willer, C, Wilsgaard, T, Wilson, J, van Wingerden, S, Winkelmann, B, Witte, D, Witteman, J, Wolffenbuttel, B, Wong, A, Wright, A, Yang, J, Yarnell, J, Zgaga, L, Zhao, J, Zillikens, M, Zitting, P, Zondervan, K, Psychiatry, EMGO - Mental health, Plastic, Reconstructive and Hand Surgery, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Biological Psychology, EMGO+ - Mental Health, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, Abecasis, GR., Absher, D., Alavere, H., Albrecht, E., Allen, HL., Almgren, P., Amin, N., Amouyel, P., Anderson, D., Arnold, AM., Arveiler, D., Aspelund, T., Asselbergs, FW., Assimes, TL., Atalay, M., Attwood, AP., Atwood, LD., Bakker, SJ., Balkau, B., Balmforth, AJ., Barlassina, C., Barroso£££Inês£££ I., Basart, H., Bauer, S., Beckmann, JS., Beilby, JP., Bennett, AJ., Ben-Shlomo, Y., Bergman, RN., Bergmann, S., Berndt, SI., Biffar, R., Di Blasio AM., Boehm, BO., Boehnke, M., Boeing, H., Boerwinkle, E., Bolton, JL., Bonnefond, A., Bonnycastle, LL., Boomsma, DI., Borecki, IB., Bornstein, SR., Bouatia-Naji, N., Boucher, G., Bragg-Gresham, JL., Brambilla, P., Bruinenberg, M., Buchanan, TA., Buechler, C., Cadby, G., Campbell, H., Caulfield, MJ., Cavalcanti-Proença, C., Cesana, G., Chanock, SJ., Chasman, DI., Chen, YD., Chines, PS., Clegg, DJ., Coin, L., Collins, FS., Connell, JM., Cookson, W., Cooper, MN., Croteau-Chonka, DC., Cupples, LA., Cusi, D., Day, FR., Day, IN., Dedoussis, GV., Dei, M., Deloukas, P., Dermitzakis, ET., Dimas, AS., Dimitriou, M., Dixon, AL., Dörr, M., van Duijn CM., Ebrahim, S., Edkins, S., Eiriksdottir, G., Eisinger, K., Eklund, N., Elliott, P., Erbel, R., Erdmann, J., Erdos, MR., Eriksson, JG., Esko£££Tõnu£££ T., Estrada, K., Evans, DM., de Faire, U., Fall, T., Farrall, M., Feitosa, MF., Ferrario, MM., Ferreira, T., Ferrières, J., Fischer, K., Fisher, E., Fowkes, G., Fox, CS., Franke, L., Franks, PW., Fraser, RM., Frau, F., Frayling, T., Freimer, NB., Froguel, P., Fu, M., Gaget, S., Ganna, A., Gejman, PV., Gentilini, D., Geus, EJ., Gieger, C., Gigante, B., Gjesing, AP., Glazer, NL., Goddard, ME., Goel, A., Grallert, H., Gräßler, J., Grönberg, H., Groop, LC., Groves, CJ., Gudnason, V., Guiducci, C., Gustafsson, S., Gyllensten, U., Hall, AS., Hall, P., Hallmans, G., Hamsten, A., Hansen, T., Haritunians, T., Harris, TB., van der Harst, P., Hartikainen, AL., Hassanali, N., Hattersley, AT., Havulinna, AS., Hayward, C., Heard-Costa, NL., Heath, AC., Hebebrand, J., Heid, IM., den Heijer, M., Hengstenberg, C., Herzig, KH., Hicks, AA., Hingorani, A., Hinney, A., Hirschhorn, JN., Hofman, A., Holmes, CC., Homuth, G., Hottenga, JJ., Hovingh, KG., Hu, FB., Hu, YJ., Huffman, JE., Hui, J., Huikuri, H., Humphries, SE., Hung, J., Hunt, SE., Hunter, D., Hveem, K., Hyppönen, E., Igl, W., Illig, T., Ingelsson, E., Iribarren, C., Isomaa, B., Jackson, AU., Jacobs, KB., James, AL., Jansson, JO., Jarick, I., Jarvelin, MR., Jöckel, KH., Johansson£££Åsa£££ Å., Johnson, T., Jolley, J., Jørgensen, T., Jousilahti, P., Jula, A., Justice, AE., Kaakinen, M., Kähönen, M., Kajantie, E., Kanoni, S., Kao, WH., Kaplan, LM., Kaplan, RC., Kaprio, J., Kapur, K., Karpe, F., Kathiresan, S., Kee, F., Keinanen-Kiukaanniemi, SM., Ketkar, S., Kettunen, J., Khaw, KT., Kiemeney, LA., Kilpeläinen, TO., Kinnunen, L., Kivimaki, M., Kivmaki, M., Van der Klauw MM., Kleber, ME., Knowles, JW., Koenig, W., Kolcic, I., Kolovou, G., König, IR., Koskinen, S., Kovacs, P., Kraft, P., Kraja, AT., Kristiansson, K., KrjutÅjkov, K., Kroemer, HK., Krohn, JP., Krzelj, V., Kuh, D., Kulzer, JR., Kumari, M., Kutalik£££Zoltán£££ Z., Kuulasmaa, K., Kuusisto, J., Kvaloy, K., Laakso, M., Laitinen, JH., Lakka, TA., Lamina, C., Langenberg, C., Lantieri, O., Lathrop, GM., Launer, LJ., Lawlor, DA., Lawrence, RW., Leach, IM., Lecoeur, C., Lee, SH., Lehtimäki, T., Leitzmann, MF., Lettre, G., Levinson, DF., Li, G., Li, S., Liang, L., Lin, DY., Lind, L., Lindgren, CM., Lindström, J., Liu, J., Liuzzi, A., Locke, AE., Lokki, ML., Loley, C., Loos, RJ., Lorentzon, M., Luan£££Jian'an£££ J., Luben, RN., Ludwig, B., Madden, PA., Mägi, R., Magnusson, PK., Mangino, M., Manunta, P., Marek, D., Marre, M., Martin, NG., März, W., Maschio, A., Mathieson, I., McArdle, WL., McCaroll, SA., McCarthy, A., McCarthy, MI., McKnight, B., Medina-Gomez, C., Medland, SE., Meitinger, T., Metspalu, A., van Meurs JB., Meyre, D., Midthjell, K., Mihailov, E., Milani, L., Min, JL., Moebus, S., Moffatt, MF., Mohlke, KL., Molony, C., Monda, KL., Montgomery, GW., Mooser, V., Morken, MA., Morris, AD., Morris, AP., Mühleisen, TW., Müller-Nurasyid, M., Munroe, PB., Musk, AW., Narisu, N., Navis, G., Neale, BM., Nelis, M., Nemesh, J., Neville, MJ., Ngwa, JS., Nicholson, G., Nieminen, MS., Njølstad, I., Nohr, EA., Nolte, IM., North, KE., Nöthen, MM., Nyholt, DR., O'Connell, JR., Ohlsson, C., Oldehinkel, AJ., van Ommen GJ., Ong, KK., Oostra, BA., Ouwehand, WH., Palmer, CN., Palmer, LJ., Palotie, A., Paré, G., Parker, AN., Paternoster, L., Pawitan, Y., Pechlivanis, S., Peden, JF., Pedersen, NL., Pedersen, O., Pellikka, N., Peltonen, L., Penninx, B., Perola, M., Perry, JR., Person, T., Peters, A., Peters, MJ., Pichler, I., Pietiläinen, KH., Platou, CG., Polasek, O., Pouta, A., Power, C., Pramstaller, PP., Preuss, M., Price, JF., Prokopenko, I., Province, MA., Psaty, BM., Purcell, S., Pütter, C., Qi, L., Quertermous, T., Radhakrishnan, A., Raitakari, O., Randall, JC., Rauramaa, R., Rayner, NW., Rehnberg, E., Rendon, A., Ridderstråle, M., Ridker, PM., Ripatti, S., Rissanen, A., Rivadeneira, F., Rivolta, C., Robertson, NR., Rose, LM., Rudan, I., Saaristo, TE., Sager, H., Salomaa, V., Samani, NJ., Sambrook, JG., Sanders, AR., Sandholt, C., Sanna, S., Saramies, J., Schadt, EE., Scherag, A., Schipf, S., Schlessinger, D., Schreiber, S., Schunkert, H., Schwarz, PE., Scott, LJ., Shi, J., Shin, SY., Shuldiner, AR., Shungin, D., Signorini, S., Silander, K., Sinisalo, J., Skrobek, B., Smit, JH., Smith, AV., Smith, GD., Snieder, H., Soranzo, N., Sørensen, TI., Sovio, U., Spector, TD., Speliotes, EK., Stančáková, A., Stark, K., Stefansson, K., Steinthorsdottir, V., Stephens, JC., Stirrups, K., Stolk, RP., Strachan, DP., Strawbridge, RJ., Stringham, HM., Stumvoll, M., Surakka, I., Swift, AJ., Syvanen, AC., Tammesoo, ML., Teder-Laving, M., Teslovich, TM., Teumer, A., Theodoraki, EV., Thomson, B., Thorand, B., Thorleifsson, G., Thorsteinsdottir, U., Timpson, NJ., Tönjes, A., Tregouet, DA., Tremoli, E., Trip, MD., Tuomi, T., Tuomilehto, J., Tyrer, J., Uda, M., Uitterlinden, AG., Usala, G., Uusitupa, M., Valle, TT., Vandenput, L., Vatin, V., Vedantam, S., de Vegt, F., Vermeulen, SH., Viikari, J., Virtamo, J., Visscher, PM., Vitart, V., Van Vliet-Ostaptchouk JV., Voight, BF., Vollenweider, P., Volpato, CB., Völzke, H., Waeber, G., Waite, LL., Wallaschofski, H., Walters, GB., Wang, Z., Wareham, NJ., Watanabe, RM., Watkins, H., Weedon, MN., Welch, R., Weyant, RJ., Wheeler, E., White, CC., Wichmann, HE., Widen, E., Wild, SH., Willemsen, G., Willer, CJ., Wilsgaard, T., Wilson, JF., van Wingerden, S., Winkelmann, BR., Winkler, TW., Witte, DR., Witteman, JC., Wolffenbuttel, BH., Wong, A., Wood, AR., Workalemahu, T., Wright, AF., Yang, J., Yarnell, JW., Zgaga, L., Zhao, JH., Zillikens, MC., Zitting, P., and Zondervan, KT.

Subjects
Quality Control, Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, media_common.quotation_subject, quality control, GWAMAS, Control (management), Medizin, Genome-wide association study, Biology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Software, SDG 17 - Partnerships for the Goals, Meta-Analysis as Topic, Comparable size, Quality (business), 030304 developmental biology, media_common, Protocol (science), 0303 health sciences, business.industry, Software package, Data science, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Genome-Wide Association Study/methods, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], quality control, genome-wide association meta-analyses, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Item does not contain fulltext Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

Published
2014

39. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.

Author

Lahti J, Tuominen S, Yang Q, Pergola G, Ahmad S, Amin N, Armstrong NJ, Beiser A, Bey K, Bis JC, Boerwinkle E, Bressler J, Campbell A, Campbell H, Chen Q, Corley J, Cox SR, Davies G, De Jager PL, Derks EM, Faul JD, Fitzpatrick AL, Fohner AE, Ford I, Fornage M, Gerring Z, Grabe HJ, Grodstein F, Gudnason V, Simonsick E, Holliday EG, Joshi PK, Kajantie E, Kaprio J, Karell P, Kleineidam L, Knol MJ, Kochan NA, Kwok JB, Leber M, Lam M, Lee T, Li S, Loukola A, Luck T, Marioni RE, Mather KA, Medland S, Mirza SS, Nalls MA, Nho K, O'Donnell A, Oldmeadow C, Painter J, Pattie A, Reppermund S, Risacher SL, Rose RJ, Sadashivaiah V, Scholz M, Satizabal CL, Schofield PW, Schraut KE, Scott RJ, Simino J, Smith AV, Smith JA, Stott DJ, Surakka I, Teumer A, Thalamuthu A, Trompet S, Turner ST, van der Lee SJ, Villringer A, Völker U, Wilson RS, Wittfeld K, Vuoksimaa E, Xia R, Yaffe K, Yu L, Zare H, Zhao W, Ames D, Attia J, Bennett DA, Brodaty H, Chasman DI, Goldman AL, Hayward C, Ikram MA, Jukema JW, Kardia SLR, Lencz T, Loeffler M, Mattay VS, Palotie A, Psaty BM, Ramirez A, Ridker PM, Riedel-Heller SG, Sachdev PS, Saykin AJ, Scherer M, Schofield PR, Sidney S, Starr JM, Trollor J, Ulrich W, Wagner M, Weir DR, Wilson JF, Wright MJ, Weinberger DR, Debette S, Eriksson JG, Mosley TH Jr, Launer LJ, van Duijn CM, Deary IJ, Seshadri S, and Räikkönen K

Subjects
Verbal Learning, Multifactorial Inheritance, Brain, Memory, Short-Term physiology, Learning
Abstract

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes., (© 2022. The Author(s).)

Published
2022
Full Text
View/download PDF

40. The HUNT study: A population-based cohort for genetic research.

Author

Brumpton BM, Graham S, Surakka I, Skogholt AH, Løset M, Fritsche LG, Wolford B, Zhou W, Nielsen JB, Holmen OL, Gabrielsen ME, Thomas L, Bhatta L, Rasheed H, Zhang H, Kang HM, Hornsby W, Moksnes MR, Coward E, Melbye M, Giskeødegård GF, Fenstad J, Krokstad S, Næss M, Langhammer A, Boehnke M, Abecasis GR, Åsvold BO, Hveem K, and Willer CJ

Abstract

The Trøndelag Health Study (HUNT) is a population-based cohort of ∼229,000 individuals recruited in four waves beginning in 1984 in Trøndelag County, Norway. Approximately 88,000 of these individuals have available genetic data from array genotyping. HUNT participants were recruited during four community-based recruitment waves and provided information on health-related behaviors, self-reported diagnoses, family history of disease, and underwent physical examinations. Linkage via the Norwegian personal identification number integrates digitized health care information from doctor visits and national health registries including death, cancer and prescription registries. Genome-wide association studies of HUNT participants have provided insights into the mechanism of cardiovascular, metabolic, osteoporotic, and liver-related diseases, among others. Unique features of this cohort that facilitate research include nearly 40 years of longitudinal follow-up in a motivated and well-educated population, family data, comprehensive phenotyping, and broad availability of DNA, RNA, urine, fecal, plasma, and serum samples., Competing Interests: G.R.A. works for Regeneron Pharmaceuticals. C.J.W.’s spouse works for Regeneron Pharmaceuticals., (© 2022 The Author(s).)

Published
2022
Full Text
View/download PDF

41. Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease.

Author

Zhou W, Kanai M, Wu KH, Rasheed H, Tsuo K, Hirbo JB, Wang Y, Bhattacharya A, Zhao H, Namba S, Surakka I, Wolford BN, Lo Faro V, Lopera-Maya EA, Läll K, Favé MJ, Partanen JJ, Chapman SB, Karjalainen J, Kurki M, Maasha M, Brumpton BM, Chavan S, Chen TT, Daya M, Ding Y, Feng YA, Guare LA, Gignoux CR, Graham SE, Hornsby WE, Ingold N, Ismail SI, Johnson R, Laisk T, Lin K, Lv J, Millwood IY, Moreno-Grau S, Nam K, Palta P, Pandit A, Preuss MH, Saad C, Setia-Verma S, Thorsteinsdottir U, Uzunovic J, Verma A, Zawistowski M, Zhong X, Afifi N, Al-Dabhani KM, Al Thani A, Bradford Y, Campbell A, Crooks K, de Bock GH, Damrauer SM, Douville NJ, Finer S, Fritsche LG, Fthenou E, Gonzalez-Arroyo G, Griffiths CJ, Guo Y, Hunt KA, Ioannidis A, Jansonius NM, Konuma T, Lee MTM, Lopez-Pineda A, Matsuda Y, Marioni RE, Moatamed B, Nava-Aguilar MA, Numakura K, Patil S, Rafaels N, Richmond A, Rojas-Muñoz A, Shortt JA, Straub P, Tao R, Vanderwerff B, Vernekar M, Veturi Y, Barnes KC, Boezen M, Chen Z, Chen CY, Cho J, Smith GD, Finucane HK, Franke L, Gamazon ER, Ganna A, Gaunt TR, Ge T, Huang H, Huffman J, Katsanis N, Koskela JT, Lajonchere C, Law MH, Li L, Lindgren CM, Loos RJF, MacGregor S, Matsuda K, Olsen CM, Porteous DJ, Shavit JA, Snieder H, Takano T, Trembath RC, Vonk JM, Whiteman DC, Wicks SJ, Wijmenga C, Wright J, Zheng J, Zhou X, Awadalla P, Boehnke M, Bustamante CD, Cox NJ, Fatumo S, Geschwind DH, Hayward C, Hveem K, Kenny EE, Lee S, Lin YF, Mbarek H, Mägi R, Martin HC, Medland SE, Okada Y, Palotie AV, Pasaniuc B, Rader DJ, Ritchie MD, Sanna S, Smoller JW, Stefansson K, van Heel DA, Walters RG, Zöllner S, Martin AR, Willer CJ, Daly MJ, and Neale BM

Abstract

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits., Competing Interests: M.J.D. is a founder of Maze Therapeutics. B.M.N. is a member of the scientific advisory board at Deep Genomics and a consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. The spouse of C.J.W. works at Regeneron Pharmaceuticals. C.-Y.C. is employed by Biogen. C.R.G. owns stock in 23andMe, Inc. T.R.G. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. E.E.K. has received speaker fees from Regeneron, Illumina, and 23andMe and is a member of the advisory board for Galateo Bio. R.E.M. has received speaker fees from Illumina and is a scientific advisor to the Epigenetic Clock Development Foundation. G.D.S. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. K.S. and U.T. are employed by deCODE Genetics/Amgen, Inc. J.Z. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. S.M. is a co-founder of and holds stock in Seonix Bio., (© 2022.)

Published
2022
Full Text
View/download PDF

42. Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis.

Author

Ruotsalainen SE, Surakka I, Mars N, Karjalainen J, Kurki M, Kanai M, Krebs K, Graham S, Mishra PP, Mishra BH, Sinisalo J, Palta P, Lehtimäki T, Raitakari O, Milani L, Okada Y, Palotie A, Widen E, Daly MJ, and Ripatti S

Subjects
Animals, Antigens, Surface, Genetic Loci, Genome-Wide Association Study, Humans, Mice, Milk Proteins genetics, Polymorphism, Single Nucleotide, Cardiovascular Diseases genetics, Coronary Artery Disease genetics, Coronary Artery Disease prevention & control
Abstract

Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland's population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In a large Finnish biobank study FinnGen, we identified an association between an inframe insertion rs534125149 in MFGE8 (encoding lactadherin) and protection against coronary atherosclerosis. This variant is highly enriched in Finland, and the protective association was replicated in meta-analysis of BioBank Japan and Estonian biobank. Additionally, we identified a protective association between splice acceptor variant rs201988637 in MFGE8 and coronary atherosclerosis, independent of the rs534125149, with no significant risk-increasing associations. This variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial aging also in humans in addition to previous evidence in mice. In conclusion, our results suggest that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially., (© 2022. The Author(s).)

Published
2022
Full Text
View/download PDF

43. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

Author

Ramdas S, Judd J, Graham SE, Kanoni S, Wang Y, Surakka I, Wenz B, Clarke SL, Chesi A, Wells A, Bhatti KF, Vedantam S, Winkler TW, Locke AE, Marouli E, Zajac GJM, Wu KH, Ntalla I, Hui Q, Klarin D, Hilliard AT, Wang Z, Xue C, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Hwang MY, Han S, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Havulinna AS, Veturi Y, Pacheco JA, Rosenthal EA, Lingren T, Feng Q, Kullo IJ, Narita A, Takayama J, Martin HC, Hunt KA, Trivedi B, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Rasheed A, Hindy G, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Choudhury A, Sengupta D, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Luan J, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Wood AR, Ji Y, Gao Z, Haworth S, Mitchell RE, Chai JF, Aadahl M, Bjerregaard AA, Yao J, Manichaikul A, Lee WJ, Hsiung CA, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Mauro P, Matteo F, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Schönherr S, Forer L, Scholz M, Galesloot TE, Bradfield JP, Ruotsalainen SE, Daw EW, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Le P, Feitosa MF, Wojczynski MK, Hemerich D, Preuss M, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Noah TL, Verma A, Slieker RC, Lo KS, Zilhao NR, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Demirkan A, Leonard HL, Marten J, Emmel C, Schmidt B, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Nongmaithem SS, Sankareswaran A, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Chen S, Liu F, Yang J, Kentistou KA, Banas B, Morgan A, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, van der Laan SW, Chitrala KN, Weiss S, Bentley AR, Doumatey AP, Adeyemo AA, Lee JY, Petersen ERB, Nielsen AA, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hidalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, He KY, Tang H, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Kawaguchi T, Thiery J, Bis JC, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Ida Chen YD, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Zimmermann ME, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Bandinelli S, Dedoussis G, Thanaraj TA, Peyser PA, Kato N, Schulze MB, Girotto G, Böger CA, Jung B, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Tusié-Luna T, Aguilar-Salinas CA, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, den Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Walker M, Scott LJ, Koistinen HA, Chandak GR, Mercader JM, Villalpando CG, Orozco L, Fornage M, Tai ES, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Jin ZB, Lu F, Hishigaki H, Lin X, März W, Gudnason V, Tardif JC, Lettre G, T Hart LM, Elders PJM, Rader DJ, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Parra EJ, Cruz M, Psaty BM, Brandslund I, Pramstaller PP, Rotimi CN, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney L, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Francesco C, Mook-Kanamori DO, Willems van Dijk K, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Huey-Herng Sheu W, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Li H, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, de Geus EJC, Cupples LA, van Meurs JBJ, Ikram A, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Tuomilehto J, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, Hazelhurst S, Ramsay M, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Baras A, Justice AE, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Tamiya G, Yamamoto M, van Heel DA, Trembath RC, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Kim BJ, Thorsteinsdottir U, Stefansson K, Zhang J, Chen YE, Ho YL, Lynch JA, Tsao PS, Chang KM, Cho K, O'Donnell CJ, Gaziano JM, Wilson P, Mohlke KL, Frayling TM, Hirschhorn JN, Kathiresan S, Boehnke M, Struan Grant, Natarajan P, Sun YV, Morris AP, Deloukas P, Peloso G, Assimes TL, Willer CJ, Zhu X, and Brown CD

Subjects
Chromatin genetics, Genomics, Humans, Lipids genetics, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics
Abstract

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology., Competing Interests: Declaration of interests G.C.-P. is currently an employee of 23andMe Inc. M.J.C. is the Chief Scientist for Genomics England, a UK Government company. B.M. Psaty serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. G. Thorleifsson, A.H., D.F.G., H. Holm, U.T., and K.S. are employees of deCODE/Amgen Inc. V.S. has received honoraria for consultations from Novo Nordisk and Sanofi and has an ongoing research collaboration with Bayer Ltd. M. McCarthy has served on advisory panels for Pfizer, NovoNordisk, and Zoe Global and has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. M. McCarthy and A. Mahajan are employees of Genentech and holders of Roche stock. M.S. receives funding from Pfizer Inc. for a project unrelated to this work. M.E.K. is employed by SYNLAB MVZ Mannheim GmbH. W.M. has received grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH , grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, and other from Synlab Holding Deutschland GmbH, all outside the submitted work. A.V.K. has served as a consultant to Sanofi, Medicines Company, Maze Pharmaceuticals, Navitor Pharmaceuticals, Verve Therapeutics, Amgen, and Color Genomics; received speaking fees from Illumina and the Novartis Institute for Biomedical Research; received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research, and reports a patent related to a genetic risk predictor (20190017119). S. Kathiresan is an employee of Verve Therapeutics and holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics. He is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; he has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest, and Medscape; and he reports patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). D.K. accepts consulting fees from Regeneron Pharmaceuticals. D.O.M.-K. is a part-time clinical research consultant for Metabolon, Inc. D. Saleheen has received support from the British Heart Foundation, Pfizer, Regeneron, Genentech, and Eli Lilly pharmaceuticals. P.N. reports investigator-initated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche / Genentech, is a co-founder of TenSixteen Bio, is a scientific advisory board member of Esperion Therapeutics, geneXwell, and TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. The spouse of C.J.W. is employed by Regeneron., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2022
Full Text
View/download PDF

44. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Author

Shrine, N. (Nick), Guyatt, A. L. (Anna L.), Erzurumluoglu, A. M. (A. Mesut), Jackson, V. E. (Victoria E.), Hobbs, B. D. (Brian D.), Melbourne, C. A. (Carl A.), Batini, C. (Chiara), Fawcett, K. A. (Katherine A.), Song, K. (Kijoung), Sakornsakolpat, P. (Phuwanat), Li, X. (Xingnan), Boxall, R. (Ruth), Reeve, N. F. (Nicola F.), Obeidat, M. (Ma'en), Zhao, J. H. (Jing Hua), Wielscher, M. (Matthias), Weiss, S. (Stefan), Kentistou, K. A. (Katherine A.), Cook, J. P. (James P.), Sun, B. B. (Benjamin B.), Zhou, J. (Jian), Hui, J. (Jennie), Karrasch, S. (Stefan), Imboden, M. (Medea), Harris, S. E. (Sarah E.), Marten, J. (Jonathan), Enroth, S. (Stefan), Kerr, S. M. (Shona M.), Surakka, I. (Ida), Vitart, V. (Veronique), Lehtimäki, T. (Terho), Allen, R. J. (Richard J.), Bakke, P. S. (Per S.), Beaty, T. H. (Terri H.), Bleecker, E. R. (Eugene R.), Bosse, Y. (Yohan), Brandsma, C.-A. (Corry-Anke), Chen, Z. (Zhengming), Crapo, J. D. (James D.), Danesh, J. (John), DeMeo, D. L. (Dawn L.), Dudbridge, F. (Frank), Ewert, R. (Ralf), Gieger, C. (Christian), Gulsvik, A. (Amund), Hansell, A. L. (Anna L.), Hao, K. (Ke), Hoffman, J. D. (Joshua D.), Hokanson, J. E. (John E.), Homuth, G. (Georg), Joshi, P. K. (Peter K.), Joubert, P. (Philippe), Langenberg, C. (Claudia), Li, X. (Xuan), Li, L. (Liming), Lin, K. (Kuang), Lind, L. (Lars), Locantore, N. (Nicholas), Luan, J. (Jian'an), Mahajan, A. (Anubha), Maranville, J. C. (Joseph C.), Murray, A. (Alison), Nickle, D. C. (David C.), Packer, R. (Richard), Parker, M. M. (Margaret M.), Paynton, M. L. (Megan L.), Porteous, D. J. (David J.), Prokopenko, D. (Dmitry), Qiao, D. (Dandi), Rawal, R. (Rajesh), Runz, H. (Heiko), Sayers, I. (Ian), Sin, D. D. (Don D.), Smith, B. H. (Blair H.), Artigas, M. S. (Maria Soler), Sparrow, D. (David), Tal-Singer, R. (Ruth), Timmers, P. R. (Paul R. H. J.), Van den Berge, M. (Maarten), Whittaker, J. C. (John C.), Woodruff, P. G. (Prescott G.), Verges-Armstrong, L. M. (Laura M.), Troyanskaya, O. G. (Olga G.), Raitakari, O. T. (Olli T.), Kähönen, M. (Mika), Polasek, O. (Ozren), Gyllensten, U. (Ulf), Rudan, I. (Igor), Deary, I. J. (Ian J.), Probst-Hensch, N. M. (Nicole M.), Schulz, H. (Holger), James, A. L. (Alan L.), Wilson, J. F. (James F.), Stubbe, B. (Beate), Zeggini, E. (Eleftheria), Järvelin, M.-R. (Marjo-Riitta), Wareham, N. (Nick), Silverman, E. K. (Edwin K.), Hayward, C. (Caroline), Morris, A. P. (Andrew P.), Butterworth, A. S. (Adam S.), Scott, R. A. (Robert A.), Walters, R. G. (Robin G.), Meyers, D. A. (Deborah A.), Cho, M. H. (Michael H.), Strachan, D. P. (David P.), Hall, I. P. (Ian P.), Tobin, M. D. (Martin D.), Wain, L. V. (Louise, V), Shrine, N. (Nick), Guyatt, A. L. (Anna L.), Erzurumluoglu, A. M. (A. Mesut), Jackson, V. E. (Victoria E.), Hobbs, B. D. (Brian D.), Melbourne, C. A. (Carl A.), Batini, C. (Chiara), Fawcett, K. A. (Katherine A.), Song, K. (Kijoung), Sakornsakolpat, P. (Phuwanat), Li, X. (Xingnan), Boxall, R. (Ruth), Reeve, N. F. (Nicola F.), Obeidat, M. (Ma'en), Zhao, J. H. (Jing Hua), Wielscher, M. (Matthias), Weiss, S. (Stefan), Kentistou, K. A. (Katherine A.), Cook, J. P. (James P.), Sun, B. B. (Benjamin B.), Zhou, J. (Jian), Hui, J. (Jennie), Karrasch, S. (Stefan), Imboden, M. (Medea), Harris, S. E. (Sarah E.), Marten, J. (Jonathan), Enroth, S. (Stefan), Kerr, S. M. (Shona M.), Surakka, I. (Ida), Vitart, V. (Veronique), Lehtimäki, T. (Terho), Allen, R. J. (Richard J.), Bakke, P. S. (Per S.), Beaty, T. H. (Terri H.), Bleecker, E. R. (Eugene R.), Bosse, Y. (Yohan), Brandsma, C.-A. (Corry-Anke), Chen, Z. (Zhengming), Crapo, J. D. (James D.), Danesh, J. (John), DeMeo, D. L. (Dawn L.), Dudbridge, F. (Frank), Ewert, R. (Ralf), Gieger, C. (Christian), Gulsvik, A. (Amund), Hansell, A. L. (Anna L.), Hao, K. (Ke), Hoffman, J. D. (Joshua D.), Hokanson, J. E. (John E.), Homuth, G. (Georg), Joshi, P. K. (Peter K.), Joubert, P. (Philippe), Langenberg, C. (Claudia), Li, X. (Xuan), Li, L. (Liming), Lin, K. (Kuang), Lind, L. (Lars), Locantore, N. (Nicholas), Luan, J. (Jian'an), Mahajan, A. (Anubha), Maranville, J. C. (Joseph C.), Murray, A. (Alison), Nickle, D. C. (David C.), Packer, R. (Richard), Parker, M. M. (Margaret M.), Paynton, M. L. (Megan L.), Porteous, D. J. (David J.), Prokopenko, D. (Dmitry), Qiao, D. (Dandi), Rawal, R. (Rajesh), Runz, H. (Heiko), Sayers, I. (Ian), Sin, D. D. (Don D.), Smith, B. H. (Blair H.), Artigas, M. S. (Maria Soler), Sparrow, D. (David), Tal-Singer, R. (Ruth), Timmers, P. R. (Paul R. H. J.), Van den Berge, M. (Maarten), Whittaker, J. C. (John C.), Woodruff, P. G. (Prescott G.), Verges-Armstrong, L. M. (Laura M.), Troyanskaya, O. G. (Olga G.), Raitakari, O. T. (Olli T.), Kähönen, M. (Mika), Polasek, O. (Ozren), Gyllensten, U. (Ulf), Rudan, I. (Igor), Deary, I. J. (Ian J.), Probst-Hensch, N. M. (Nicole M.), Schulz, H. (Holger), James, A. L. (Alan L.), Wilson, J. F. (James F.), Stubbe, B. (Beate), Zeggini, E. (Eleftheria), Järvelin, M.-R. (Marjo-Riitta), Wareham, N. (Nick), Silverman, E. K. (Edwin K.), Hayward, C. (Caroline), Morris, A. P. (Andrew P.), Butterworth, A. S. (Adam S.), Scott, R. A. (Robert A.), Walters, R. G. (Robin G.), Meyers, D. A. (Deborah A.), Cho, M. H. (Michael H.), Strachan, D. P. (David P.), Hall, I. P. (Ian P.), Tobin, M. D. (Martin D.), and Wain, L. V. (Louise, V)

Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function–associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Published
2019

45. Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Author

Leeuwen, Elisa, Sabo, A, Bis, JC, Huffman, JE, Manichaikul, A, Smith, AV, Feitosa, MF, Demissie, S, Joshi, PK, Duan, Q, Marten, J, van Klinken, JB, Surakka, I, Nolte, IM, Zhang, WH, Mbarek, H, Li-Gao, RF, Trompet, S, Verweij, N, Evangelou, E, Lyytikainen, LP, Tayo, BO, Deelen, J, van der Most, PJ, van der Laan, SW, Arking, DE, Morrison, A, Dehghan, Abbas, Franco Duran, OH, Hofman, Bert, Rivadeneira, Fernando, Sijbrands, E.J.G., Uitterlinden, André, Mychaleckyj, JC, Campbell, A (Archie), Hocking, LJ, Padmanabhan, S, Brody, JA, Rice, KM, White, CC, Harris, T, Isaacs, Aaron, Campbell, H, Lange, LA, Rudan, I, Kolcic, I, Navarro, P, Zemunik, T, Salomaa, V, Kooner, AS, Kooner, JS, Lehne, B, Scott, WR, Tan, ST, de Geus, EJ, Milaneschi, Y, Penninx, BWJH, Willemsen, G, de Mutsert, R, Ford, I, Gansevoort, RT, Segura-Lepe, M P, Raitakari, OT, Viikari, JS, Nikus, K, Forrester, T, McKenzie, CA, de Craen, AJM, den Ruijter, HM, Pasterkamp, G, Snieder, H, Oldehinkel, AJ, Slagboom, PE (Eline), Cooper, RS, Kahonen, M, Lehtimaki, T, Elliott, P, van der Harst, P, Jukema, JW, Mook-Kanamori, DO, Boomsma, DI, Chambers, JC, Swertz, M, Ripatti, S, van Dijk, KW, Vitart, V, Polasek, O, Hayward, C, Wilson, JG, Wilson, JF, Gudnason, V, Rich, SS, Psaty, BM, Borecki, IB, Boerwinkle, E, Rotter, JI, Cupples, LA, Duijn, Cornelia, Leeuwen, Elisa, Sabo, A, Bis, JC, Huffman, JE, Manichaikul, A, Smith, AV, Feitosa, MF, Demissie, S, Joshi, PK, Duan, Q, Marten, J, van Klinken, JB, Surakka, I, Nolte, IM, Zhang, WH, Mbarek, H, Li-Gao, RF, Trompet, S, Verweij, N, Evangelou, E, Lyytikainen, LP, Tayo, BO, Deelen, J, van der Most, PJ, van der Laan, SW, Arking, DE, Morrison, A, Dehghan, Abbas, Franco Duran, OH, Hofman, Bert, Rivadeneira, Fernando, Sijbrands, E.J.G., Uitterlinden, André, Mychaleckyj, JC, Campbell, A (Archie), Hocking, LJ, Padmanabhan, S, Brody, JA, Rice, KM, White, CC, Harris, T, Isaacs, Aaron, Campbell, H, Lange, LA, Rudan, I, Kolcic, I, Navarro, P, Zemunik, T, Salomaa, V, Kooner, AS, Kooner, JS, Lehne, B, Scott, WR, Tan, ST, de Geus, EJ, Milaneschi, Y, Penninx, BWJH, Willemsen, G, de Mutsert, R, Ford, I, Gansevoort, RT, Segura-Lepe, M P, Raitakari, OT, Viikari, JS, Nikus, K, Forrester, T, McKenzie, CA, de Craen, AJM, den Ruijter, HM, Pasterkamp, G, Snieder, H, Oldehinkel, AJ, Slagboom, PE (Eline), Cooper, RS, Kahonen, M, Lehtimaki, T, Elliott, P, van der Harst, P, Jukema, JW, Mook-Kanamori, DO, Boomsma, DI, Chambers, JC, Swertz, M, Ripatti, S, van Dijk, KW, Vitart, V, Polasek, O, Hayward, C, Wilson, JG, Wilson, JF, Gudnason, V, Rich, SS, Psaty, BM, Borecki, IB, Boerwinkle, E, Rotter, JI, Cupples, LA, and Duijn, Cornelia

Published
2016

46. How Communicating Polygenic and Clinical Risk for Atherosclerotic Cardiovascular Disease Impacts Health Behavior: an Observational Follow-up Study.

Author

Widén E, Junna N, Ruotsalainen S, Surakka I, Mars N, Ripatti P, Partanen JJ, Aro J, Mustonen P, Tuomi T, Palotie A, Salomaa V, Kaprio J, Partanen J, Hotakainen K, Pöllänen P, and Ripatti S

Subjects
Female, Follow-Up Studies, Health Behavior, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Atherosclerosis genetics, Cardiovascular Diseases genetics
Abstract

Background: Prediction tools that combine polygenic risk scores with clinical factors provide a new opportunity for improved prediction and prevention of atherosclerotic cardiovascular disease, but the clinical utility of polygenic risk score has remained unclear., Methods: We collected a prospective cohort of 7342 individuals (64% women, mean age 56 years) and estimated their 10-year risk for atherosclerotic cardiovascular disease both by a traditional risk score and a composite score combining the effect of a polygenic risk score and clinical risk factors. We then tested how returning the personal risk information with an interactive web-tool impacted on the participants' health behavior., Results: When reassessed after 1.5 years by a clinical visit and questionnaires, 20.8% of individuals at high (>10%) 10-year atherosclerotic cardiovascular disease risk had seen a doctor, 12.4% reported weight loss, 14.2% of smokers had quit smoking, and 15.4% had signed up for health coaching online. Altogether, 42.6% of persons at high risk had made one or more health behavioral changes versus 33.5% of persons at low/average risk such that higher baseline risk predicted a favorable change (OR [CI], 1.53 [1.37-1.72] for persons at high risk versus the rest, P <0.001), with both high clinical ( P <0.001) and genomic risk (OR [CI], 1.10 [1.03-1.17], P =0.003) contributing independently., Conclusions: Web-based communication of personal atherosclerotic cardiovascular disease risk-data including polygenic risk to middle-aged persons motivates positive changes in health behavior and the propensity to seek care. It supports integration of genomic information into clinical risk calculators as a feasible approach to enhance disease prevention.

Published
2022
Full Text
View/download PDF

49. Author Correction: GWAS of thyroid stimulating hormone highlights the pleiotropic effects and inverse association with thyroid cancer.

Author

Zhou W, Brumpton B, Kabil O, Gudmundsson J, Thorleifsson G, Weinstock J, Zawistowski M, Nielsen JB, Chaker L, Medici M, Teumer A, Naitza S, Sanna S, Schultheiss UT, Cappola A, Karjalainen J, Kurki M, Oneka M, Taylor P, Fritsche LG, Graham SE, Wolford BN, Overton W, Rasheed H, Haug EB, Gabrielsen ME, Skogholt AH, Surakka I, Davey Smith G, Pandit A, Roychowdhury T, Hornsby WE, Jonasson JG, Senter L, Liyanarachchi S, Ringel MD, Xu L, Kiemeney LA, He H, Netea-Maier RT, Mayordomo JI, Plantinga TS, Hrafnkelsson J, Hjartarson H, Sturgis EM, Palotie A, Daly M, Citterio CE, Arvan P, Brummett CM, Boehnke M, de la Chapelle A, Stefansson K, Hveem K, Willer CJ, and Åsvold BO

Published
2021
Full Text
View/download PDF

50. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation

Author

Horikoshi, M, Magi, R, van de Bunt, M, Surakka, I, Sarin, AP, Mahajan, A, Marullo, L, Thorleifsson, G, Hagg, S, Hottenga, JJ (Jouke Jan), Ladenvall, C, Ried, JS, Winkler, TW, Willems, SM, Pervjakova, N, Esko, T, Beekman, M, Nelson, CP, Willenborg, C, Wiltshire, S, Ferreira, T, Fernandez, J, Gaulton, KJ, Steinthorsdottir, V, Hamsten, A, Magnusson, PKE, Willemsen, G, Milaneschi, Y, Robertson, NR, Groves, CJ, Bennett, AJ, Lehtimaki, T, Viikari, JS, Rung, J, Lyssenko, V, Perola, M, Heid, IM, Herder, Cindy, Grallert, H, Muller-Nurasyid, M, Roden, M, Hypponen, E, Isaacs, Aaron, Leeuwen, Elisa, Karssen, Lennart, Mihailov, E, Houwing-Duistermaat, JJ, de Craen, AJM, Deelen, J, Havulinna, AS, Blades, M, Hengstenberg, C, Erdmann, J, Schunkert, H, Kaprio, J, Tobin, MD, Samani, NJ, Lind, L, Salomaa, V, Lindgren, CM, Slagboom, PE (Eline), Metspalu, A, Duijn, Cornelia, Eriksson, JG, Peters, A, Gieger, C, Jula, A, Groop, L, Raitakari, OT, Power, C, Penninx, BWJH, de Geus, ED, Smit, JH, Boomsma, DI, Pedersen, NL, Ingelsson, E, Thorsteinsdottir, U, Stefansson, K, Ripatti, S, Prokopenko, I, McCarthy, MI, Morris, AP, Horikoshi, M, Magi, R, van de Bunt, M, Surakka, I, Sarin, AP, Mahajan, A, Marullo, L, Thorleifsson, G, Hagg, S, Hottenga, JJ (Jouke Jan), Ladenvall, C, Ried, JS, Winkler, TW, Willems, SM, Pervjakova, N, Esko, T, Beekman, M, Nelson, CP, Willenborg, C, Wiltshire, S, Ferreira, T, Fernandez, J, Gaulton, KJ, Steinthorsdottir, V, Hamsten, A, Magnusson, PKE, Willemsen, G, Milaneschi, Y, Robertson, NR, Groves, CJ, Bennett, AJ, Lehtimaki, T, Viikari, JS, Rung, J, Lyssenko, V, Perola, M, Heid, IM, Herder, Cindy, Grallert, H, Muller-Nurasyid, M, Roden, M, Hypponen, E, Isaacs, Aaron, Leeuwen, Elisa, Karssen, Lennart, Mihailov, E, Houwing-Duistermaat, JJ, de Craen, AJM, Deelen, J, Havulinna, AS, Blades, M, Hengstenberg, C, Erdmann, J, Schunkert, H, Kaprio, J, Tobin, MD, Samani, NJ, Lind, L, Salomaa, V, Lindgren, CM, Slagboom, PE (Eline), Metspalu, A, Duijn, Cornelia, Eriksson, JG, Peters, A, Gieger, C, Jula, A, Groop, L, Raitakari, OT, Power, C, Penninx, BWJH, de Geus, ED, Smit, JH, Boomsma, DI, Pedersen, NL, Ingelsson, E, Thorsteinsdottir, U, Stefansson, K, Ripatti, S, Prokopenko, I, McCarthy, MI, and Morris, AP

Abstract

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency >= 0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Published
2015

Catalog

Books, media, physical & digital resources
See catalog results