Dataset Information

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

ABSTRACT: We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

SUBMITTER: Liu DJ

PROVIDER: S-EPMC5709146 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Liu Dajiang J DJ Peloso Gina M GM Yu Haojie H Butterworth Adam S AS Wang Xiao X Mahajan Anubha A Saleheen Danish D Emdin Connor C Alam Dewan D Alves Alexessander Couto AC Amouyel Philippe P Di Angelantonio Emanuele E Arveiler Dominique D Assimes Themistocles L TL Auer Paul L PL Baber Usman U Ballantyne Christie M CM Bang Lia E LE Benn Marianne M Bis Joshua C JC Boehnke Michael M Boerwinkle Eric E Bork-Jensen Jette J Bottinger Erwin P EP Brandslund Ivan I Brown Morris M Busonero Fabio F Caulfield Mark J MJ Chambers John C JC Chasman Daniel I DI Chen Y Eugene YE Chen Yii-Der Ida YI Chowdhury Rajiv R Christensen Cramer C Chu Audrey Y AY Connell John M JM Cucca Francesco F Cupples L Adrienne LA Damrauer Scott M SM Davies Gail G Deary Ian J IJ Dedoussis George G Denny Joshua C JC Dominiczak Anna A Dubé Marie-Pierre MP Ebeling Tapani T Eiriksdottir Gudny G Esko Tõnu T Farmaki Aliki-Eleni AE Feitosa Mary F MF Ferrario Marco M Ferrieres Jean J Ford Ian I Fornage Myriam M Franks Paul W PW Frayling Timothy M TM Frikke-Schmidt Ruth R Fritsche Lars G LG Frossard Philippe P Fuster Valentin V Ganesh Santhi K SK Gao Wei W Garcia Melissa E ME Gieger Christian C Giulianini Franco F Goodarzi Mark O MO Grallert Harald H Grarup Niels N Groop Leif L Grove Megan L ML Gudnason Vilmundur V Hansen Torben T Harris Tamara B TB Hayward Caroline C Hirschhorn Joel N JN Holmen Oddgeir L OL Huffman Jennifer J Huo Yong Y Hveem Kristian K Jabeen Sehrish S Jackson Anne U AU Jakobsdottir Johanna J Jarvelin Marjo-Riitta MR Jensen Gorm B GB Jørgensen Marit E ME Jukema J Wouter JW Justesen Johanne M JM Kamstrup Pia R PR Kanoni Stavroula S Karpe Fredrik F Kee Frank F Khera Amit V AV Klarin Derek D Koistinen Heikki A HA Kooner Jaspal S JS Kooperberg Charles C Kuulasmaa Kari K Kuusisto Johanna J Laakso Markku M Lakka Timo T Langenberg Claudia C Langsted Anne A Launer Lenore J LJ Lauritzen Torsten T Liewald David C M DCM Lin Li An LA Linneberg Allan A Loos Ruth J F RJF Lu Yingchang Y Lu Xiangfeng X Mägi Reedik R Malarstig Anders A Manichaikul Ani A Manning Alisa K AK Mäntyselkä Pekka P Marouli Eirini E Masca Nicholas G D NGD Maschio Andrea A Meigs James B JB Melander Olle O Metspalu Andres A Morris Andrew P AP Morrison Alanna C AC Mulas Antonella A Müller-Nurasyid Martina M Munroe Patricia B PB Neville Matt J MJ Nielsen Jonas B JB Nielsen Sune F SF Nordestgaard Børge G BG Ordovas Jose M JM Mehran Roxana R O'Donnell Christoper J CJ Orho-Melander Marju M Molony Cliona M CM Muntendam Pieter P Padmanabhan Sandosh S Palmer Colin N A CNA Pasko Dorota D Patel Aniruddh P AP Pedersen Oluf O Perola Markus M Peters Annette A Pisinger Charlotta C Pistis Giorgio G Polasek Ozren O Poulter Neil N Psaty Bruce M BM Rader Daniel J DJ Rasheed Asif A Rauramaa Rainer R Reilly Dermot F DF Reiner Alex P AP Renström Frida F Rich Stephen S SS Ridker Paul M PM Rioux John D JD Robertson Neil R NR Roden Dan M DM Rotter Jerome I JI Rudan Igor I Salomaa Veikko V Samani Nilesh J NJ Sanna Serena S Sattar Naveed N Schmidt Ellen M EM Scott Robert A RA Sever Peter P Sevilla Raquel S RS Shaffer Christian M CM Sim Xueling X Sivapalaratnam Suthesh S Small Kerrin S KS Smith Albert V AV Smith Blair H BH Somayajula Sangeetha S Southam Lorraine L Spector Timothy D TD Speliotes Elizabeth K EK Starr John M JM Stirrups Kathleen E KE Stitziel Nathan N Strauch Konstantin K Stringham Heather M HM Surendran Praveen P Tada Hayato H Tall Alan R AR Tang Hua H Tardif Jean-Claude JC Taylor Kent D KD Trompet Stella S Tsao Philip S PS Tuomilehto Jaakko J Tybjaerg-Hansen Anne A van Zuydam Natalie R NR Varbo Anette A Varga Tibor V TV Virtamo Jarmo J Waldenberger Melanie M Wang Nan N Wareham Nick J NJ Warren Helen R HR Weeke Peter E PE Weinstock Joshua J Wessel Jennifer J Wilson James G JG Wilson Peter W F PWF Xu Ming M Yaghootkar Hanieh H Young Robin R Zeggini Eleftheria E Zhang He H Zheng Neil S NS Zhang Weihua W Zhang Yan Y Zhou Wei W Zhou Yanhua Y Zoledziewska Magdalena M Howson Joanna M M JMM Danesh John J McCarthy Mark I MI Cowan Chad A CA Abecasis Goncalo G Deloukas Panos P Musunuru Kiran K Willer Cristen J CJ Kathiresan Sekar S

Nature genetics 20171030 12

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia t ...[more]

PMID: 29083408

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Project description:BackgroundImpaired lung function is predictive of mortality and is a key component of chronic obstructive pulmonary disease. Lung function has a strong genetic component but is also affected by environmental factors such as increased exposure to air pollution, but the effect of their interactions is not well understood.ObjectivesTo identify interactions between genetic variants and air pollution measures which affect COPD risk and lung function. Additionally, to determine whether previously identified lung function genetic association signals showed evidence of interaction with air pollution, considering both individual effects and combined effects using a genetic risk score (GRS).MethodsWe conducted a genome-wide gene-air pollution interaction analysis of spirometry measures with three measures of air pollution at home address: particulate matter (PM2.5 & PM10) and nitrogen dioxide (NO2), in approximately 300,000 unrelated European individuals from UK Biobank. We explored air pollution interactions with previously identified lung function signals and determined their combined interaction effect using a GRS.ResultsWe identified seven new genome-wide interaction signals (P<5×10-8), and a further ten suggestive interaction signals (P<5×10-7). Additionally, we found statistical evidence of interaction for FEV1/FVC between PM2.5 and previously identified lung function signal, rs10841302, near AEBP2, suggesting increased susceptibility as copies of the G allele increased (but size of the impact was small - interaction beta: -0.363 percentage points, 95% CI: -0.523, -0.203 per 5 µg/m3). There was no observed interaction between air pollutants and the weighted GRS.DiscussionWe carried out the largest genome-wide gene-air pollution interaction study of lung function and identified potential effects of clinically relevant size and significance. We observed up to 440 ml lower lung function for certain genotypes when exposed to mean levels of outdoor air pollution, which is approximately equivalent to nine years of average normal loss of lung function in adults.

Project description:The aim of the study was to identify genetic variants associated with personal best scores in Turkish track and field athletes and to compare allelic frequencies between sprint/power and endurance athletes and controls using a whole-exome sequencing (WES) approach, followed by replication studies in independent cohorts. The discovery phase involved 60 elite Turkish athletes (31 sprint/power and 29 endurance) and 20 ethnically matched controls. The replication phase involved 1132 individuals (115 elite Russian sprinters, 373 elite Russian endurance athletes (of which 75 athletes were with VO2max measurements), 209 controls, 148 Russian and 287 Finnish individuals with muscle fiber composition and cross-sectional area (CSA) data). None of the single nucleotide polymorphisms (SNPs) reached an exome-wide significance level (p < 2.3 × 10-7) in genotype-phenotype and case-control studies of Turkish athletes. However, of the 53 nominally (p < 0.05) associated SNPs, four functional variants were replicated. The SIRT1 rs41299232 G allele was significantly over-represented in Turkish (p = 0.047) and Russian (p = 0.018) endurance athletes compared to sprint/power athletes and was associated with increased VO2max (p = 0.037) and a greater proportion of slow-twitch muscle fibers (p = 0.035). The NUP210 rs2280084 A allele was significantly over-represented in Turkish (p = 0.044) and Russian (p = 0.012) endurance athletes compared to sprint/power athletes. The TRPM2 rs1785440 G allele was significantly over-represented in Turkish endurance athletes compared to sprint/power athletes (p = 0.034) and was associated with increased VO2max (p = 0.008). The AGRN rs4074992 C allele was significantly over-represented in Turkish sprint/power athletes compared to endurance athletes (p = 0.037) and was associated with a greater CSA of fast-twitch muscle fibers (p = 0.024). In conclusion, we present the first WES study of athletes showing that this approach can be used to identify novel genetic markers associated with exercise- and sport-related phenotypes.

Dataset Information

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

Publications

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

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