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1. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Author

Warrington NM, Beaumont RN, Horikoshi M, Day FR, Helgeland Ø, Laurin C, Bacelis J, Peng S, Hao K, Feenstra B, Wood AR, Mahajan A, Tyrrell J, Robertson NR, Rayner NW, Qiao Z, Moen GH, Vaudel M, Marsit CJ, Chen J, Nodzenski M, Schnurr TM, Zafarmand MH, Bradfield JP, Grarup N, Kooijman MN, Li-Gao R, Geller F, Ahluwalia TS, Paternoster L, Rueedi R, Huikari V, Hottenga JJ, Lyytikäinen LP, Cavadino A, Metrustry S, Cousminer DL, Wu Y, Thiering E, Wang CA, Have CT, Vilor-Tejedor N, Joshi PK, Painter JN, Ntalla I, Myhre R, Pitkänen N, van Leeuwen EM, Joro R, Lagou V, Richmond RC, Espinosa A, Barton SJ, Inskip HM, Holloway JW, Santa-Marina L, Estivill X, Ang W, Marsh JA, Reichetzeder C, Marullo L, Hocher B, Lunetta KL, Murabito JM, Relton CL, Kogevinas M, Chatzi L, Allard C, Bouchard L, Hivert MF, Zhang G, Muglia LJ, Heikkinen J, Morgen CS, van Kampen AHC, van Schaik BDC, Mentch FD, Langenberg C, Luan J, Scott RA, Zhao JH, Hemani G, Ring SM, Bennett AJ, Gaulton KJ, Fernandez-Tajes J, van Zuydam NR, Medina-Gomez C, de Haan HG, Rosendaal FR, Kutalik Z, Marques-Vidal P, Das S, Willemsen G, Mbarek H, Müller-Nurasyid M, Standl M, Appel EVR, Fonvig CE, Trier C, van Beijsterveldt CEM, Murcia M, Bustamante M, Bonas-Guarch S, Hougaard DM, Mercader JM, Linneberg A, Schraut KE, Lind PA, Medland SE, Shields BM, Knight BA, Chai JF, Panoutsopoulou K, Bartels M, Sánchez F, Stokholm J, Torrents D, Vinding RK, Willems SM, Atalay M, Chawes BL, Kovacs P, Prokopenko I, Tuke MA, Yaghootkar H, Ruth KS, Jones SE, Loh PR, Murray A, Weedon MN, Tönjes A, Stumvoll M, Michaelsen KF, Eloranta AM, Lakka TA, van Duijn CM, Kiess W, Körner A, Niinikoski H, Pahkala K, Raitakari OT, Jacobsson B, Zeggini E, Dedoussis GV, Teo YY, Saw SM, Montgomery GW, Campbell H, Wilson JF, Vrijkotte TGM, Vrijheid M, de Geus EJCN, Hayes MG, Kadarmideen HN, Holm JC, Beilin LJ, Pennell CE, Heinrich J, Adair LS, Borja JB, Mohlke KL, Eriksson JG, Widén EE, Hattersley AT, Spector TD, Kähönen M, Viikari JS, Lehtimäki T, Boomsma DI, Sebert S, Vollenweider P, Sørensen TIA, Bisgaard H, Bønnelykke K, Murray JC, Melbye M, Nohr EA, Mook-Kanamori DO, Rivadeneira F, Hofman A, Felix JF, Jaddoe VWV, Hansen T, Pisinger C, Vaag AA, Pedersen O, Uitterlinden AG, Järvelin MR, Power C, Hyppönen E, Scholtens DM, Lowe WL Jr, Davey Smith G, Timpson NJ, Morris AP, Wareham NJ, Hakonarson H, Grant SFA, Frayling TM, Lawlor DA, Njølstad PR, Johansson S, Ong KK, McCarthy MI, Perry JRB, Evans DM, and Freathy RM

Subjects
Adult, Blood Pressure genetics, Body Height genetics, Diabetes Mellitus, Type 2 etiology, Diabetes Mellitus, Type 2 genetics, Female, Fetal Development genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Diseases etiology, Heart Diseases genetics, Humans, Infant, Newborn, Male, Maternal Inheritance genetics, Maternal-Fetal Exchange genetics, Metabolic Diseases etiology, Metabolic Diseases genetics, Models, Genetic, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors, Birth Weight genetics
Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Published
2019
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2. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis.

Author

Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE, Zheng J, Gregson CL, Grundberg E, Trajanoska K, Logan JG, Pollard AS, Sparkes PC, Ghirardello EJ, Allen R, Leitch VD, Butterfield NC, Komla-Ebri D, Adoum AT, Curry KF, White JK, Kussy F, Greenlaw KM, Xu C, Harvey NC, Cooper C, Adams DJ, Greenwood CMT, Maurano MT, Kaptoge S, Rivadeneira F, Tobias JH, Croucher PI, Ackert-Bicknell CL, Bassett JHD, Williams GR, Richards JB, and Evans DM

Subjects
Animals, Disease Models, Animal, Female, Femur chemistry, Gene Expression Profiling, Glypicans deficiency, Glypicans genetics, Glypicans physiology, Growth Disorders genetics, Humans, Male, Mice, Mice, Knockout, Molecular Sequence Annotation, Osteoblasts metabolism, Osteochondrodysplasias congenital, Osteochondrodysplasias genetics, Osteoclasts metabolism, Osteocytes metabolism, Osteoporosis pathology, Phenotype, Bone Density genetics, Calcaneus pathology, Genome-Wide Association Study, Osteoporosis genetics, Polymorphism, Single Nucleotide
Abstract

Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.

Published
2017
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3. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.

Author

Bønnelykke K, Matheson MC, Pers TH, Granell R, Strachan DP, Alves AC, Linneberg A, Curtin JA, Warrington NM, Standl M, Kerkhof M, Jonsdottir I, Bukvic BK, Kaakinen M, Sleimann P, Thorleifsson G, Thorsteinsdottir U, Schramm K, Baltic S, Kreiner-Møller E, Simpson A, St Pourcain B, Coin L, Hui J, Walters EH, Tiesler CMT, Duffy DL, Jones G, Ring SM, McArdle WL, Price L, Robertson CF, Pekkanen J, Tang CS, Thiering E, Montgomery GW, Hartikainen AL, Dharmage SC, Husemoen LL, Herder C, Kemp JP, Elliot P, James A, Waldenberger M, Abramson MJ, Fairfax BP, Knight JC, Gupta R, Thompson PJ, Holt P, Sly P, Hirschhorn JN, Blekic M, Weidinger S, Hakonarsson H, Stefansson K, Heinrich J, Postma DS, Custovic A, Pennell CE, Jarvelin MR, Koppelman GH, Timpson N, Ferreira MA, Bisgaard H, and Henderson AJ

Subjects
Alleles, Computational Biology, Gene Regulatory Networks, Genomics, Humans, Hypersensitivity metabolism, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Signal Transduction, Genetic Loci, Genome-Wide Association Study, Hypersensitivity genetics
Abstract

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

Published
2013
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4. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Author

Horikoshi M, Yaghootkar H, Mook-Kanamori DO, Sovio U, Taal HR, Hennig BJ, Bradfield JP, St Pourcain B, Evans DM, Charoen P, Kaakinen M, Cousminer DL, Lehtimäki T, Kreiner-Møller E, Warrington NM, Bustamante M, Feenstra B, Berry DJ, Thiering E, Pfab T, Barton SJ, Shields BM, Kerkhof M, van Leeuwen EM, Fulford AJ, Kutalik Z, Zhao JH, den Hoed M, Mahajan A, Lindi V, Goh LK, Hottenga JJ, Wu Y, Raitakari OT, Harder MN, Meirhaeghe A, Ntalla I, Salem RM, Jameson KA, Zhou K, Monies DM, Lagou V, Kirin M, Heikkinen J, Adair LS, Alkuraya FS, Al-Odaib A, Amouyel P, Andersson EA, Bennett AJ, Blakemore AI, Buxton JL, Dallongeville J, Das S, de Geus EJ, Estivill X, Flexeder C, Froguel P, Geller F, Godfrey KM, Gottrand F, Groves CJ, Hansen T, Hirschhorn JN, Hofman A, Hollegaard MV, Hougaard DM, Hyppönen E, Inskip HM, Isaacs A, Jørgensen T, Kanaka-Gantenbein C, Kemp JP, Kiess W, Kilpeläinen TO, Klopp N, Knight BA, Kuzawa CW, McMahon G, Newnham JP, Niinikoski H, Oostra BA, Pedersen L, Postma DS, Ring SM, Rivadeneira F, Robertson NR, Sebert S, Simell O, Slowinski T, Tiesler CM, Tönjes A, Vaag A, Viikari JS, Vink JM, Vissing NH, Wareham NJ, Willemsen G, Witte DR, Zhang H, Zhao J, Wilson JF, Stumvoll M, Prentice AM, Meyer BF, Pearson ER, Boreham CA, Cooper C, Gillman MW, Dedoussis GV, Moreno LA, Pedersen O, Saarinen M, Mohlke KL, Boomsma DI, Saw SM, Lakka TA, Körner A, Loos RJ, Ong KK, Vollenweider P, van Duijn CM, Koppelman GH, Hattersley AT, Holloway JW, Hocher B, Heinrich J, Power C, Melbye M, Guxens M, Pennell CE, Bønnelykke K, Bisgaard H, Eriksson JG, Widén E, Hakonarson H, Uitterlinden AG, Pouta A, Lawlor DA, Smith GD, Frayling TM, McCarthy MI, Grant SF, Jaddoe VW, Jarvelin MR, Timpson NJ, Prokopenko I, and Freathy RM

Subjects
Adult, Blood Pressure genetics, Diabetes Mellitus, Type 2 genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Newborn, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Birth Weight genetics, Body Height genetics, Fetal Development genetics, Genetic Linkage, Quantitative Trait Loci
Abstract

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Published
2013
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5. A genome-wide association meta-analysis identifies new childhood obesity loci.

Author

Bradfield JP, Taal HR, Timpson NJ, Scherag A, Lecoeur C, Warrington NM, Hypponen E, Holst C, Valcarcel B, Thiering E, Salem RM, Schumacher FR, Cousminer DL, Sleiman PM, Zhao J, Berkowitz RI, Vimaleswaran KS, Jarick I, Pennell CE, Evans DM, St Pourcain B, Berry DJ, Mook-Kanamori DO, Hofman A, Rivadeneira F, Uitterlinden AG, van Duijn CM, van der Valk RJ, de Jongste JC, Postma DS, Boomsma DI, Gauderman WJ, Hassanein MT, Lindgren CM, Mägi R, Boreham CA, Neville CE, Moreno LA, Elliott P, Pouta A, Hartikainen AL, Li M, Raitakari O, Lehtimäki T, Eriksson JG, Palotie A, Dallongeville J, Das S, Deloukas P, McMahon G, Ring SM, Kemp JP, Buxton JL, Blakemore AI, Bustamante M, Guxens M, Hirschhorn JN, Gillman MW, Kreiner-Møller E, Bisgaard H, Gilliland FD, Heinrich J, Wheeler E, Barroso I, O'Rahilly S, Meirhaeghe A, Sørensen TI, Power C, Palmer LJ, Hinney A, Widen E, Farooqi IS, McCarthy MI, Froguel P, Meyre D, Hebebrand J, Jarvelin MR, Jaddoe VW, Smith GD, Hakonarson H, and Grant SF

Subjects
Adolescent, Adult, Body Mass Index, Case-Control Studies, Genetic Predisposition to Disease, Humans, Young Adult, Genetic Loci, Genetic Markers, Genome-Wide Association Study, Obesity genetics, Polymorphism, Single Nucleotide genetics
Abstract

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).

Published
2012
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6. Common variants at 12q15 and 12q24 are associated with infant head circumference.

Author

Taal HR, Pourcain BS, Thiering E, Das S, Mook-Kanamori DO, Warrington NM, Kaakinen M, Kreiner-Møller E, Bradfield JP, Freathy RM, Geller F, Guxens M, Cousminer DL, Kerkhof M, Timpson NJ, Ikram MA, Beilin LJ, Bønnelykke K, Buxton JL, Charoen P, Chawes BLK, Eriksson J, Evans DM, Hofman A, Kemp JP, Kim CE, Klopp N, Lahti J, Lye SJ, McMahon G, Mentch FD, Müller M, O'Reilly PF, Prokopenko I, Rivadeneira F, Steegers EAP, Sunyer J, Tiesler C, Yaghootkar H, Breteler MMB, Debette S, Fornage M, Gudnason V, Launer LJ, van der Lugt A, Mosley TH, Seshadri S, Smith AV, Vernooij MW, Blakemore AI, Chiavacci RM, Feenstra B, Fernandez-Benet J, Grant SFA, Hartikainen AL, van der Heijden AJ, Iñiguez C, Lathrop M, McArdle WL, Mølgaard A, Newnham JP, Palmer LJ, Palotie A, Pouta A, Ring SM, Sovio U, Standl M, Uitterlinden AG, Wichmann HE, Vissing NH, DeCarli C, van Duijn CM, McCarthy MI, Koppelman GH, Estivill X, Hattersley AT, Melbye M, Bisgaard H, Pennell CE, Widen E, Hakonarson H, Smith GD, Heinrich J, Jarvelin MR, and Jaddoe VWV

Subjects
Female, Humans, Infant, Male, Pregnancy, Genetic Loci, Genetic Markers, Genome-Wide Association Study, Chromosomes, Human, Pair 12 genetics, Head growth & development, Head pathology, Polymorphism, Single Nucleotide genetics, Pregnancy Complications etiology, Pregnancy Complications pathology, White People genetics
Abstract

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

Published
2012
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7. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis.

Author

Paternoster L, Standl M, Chen CM, Ramasamy A, Bønnelykke K, Duijts L, Ferreira MA, Alves AC, Thyssen JP, Albrecht E, Baurecht H, Feenstra B, Sleiman PM, Hysi P, Warrington NM, Curjuric I, Myhre R, Curtin JA, Groen-Blokhuis MM, Kerkhof M, Sääf A, Franke A, Ellinghaus D, Fölster-Holst R, Dermitzakis E, Montgomery SB, Prokisch H, Heim K, Hartikainen AL, Pouta A, Pekkanen J, Blakemore AI, Buxton JL, Kaakinen M, Duffy DL, Madden PA, Heath AC, Montgomery GW, Thompson PJ, Matheson MC, Le Souëf P, St Pourcain B, Smith GD, Henderson J, Kemp JP, Timpson NJ, Deloukas P, Ring SM, Wichmann HE, Müller-Nurasyid M, Novak N, Klopp N, Rodríguez E, McArdle W, Linneberg A, Menné T, Nohr EA, Hofman A, Uitterlinden AG, van Duijn CM, Rivadeneira F, de Jongste JC, van der Valk RJ, Wjst M, Jogi R, Geller F, Boyd HA, Murray JC, Kim C, Mentch F, March M, Mangino M, Spector TD, Bataille V, Pennell CE, Holt PG, Sly P, Tiesler CM, Thiering E, Illig T, Imboden M, Nystad W, Simpson A, Hottenga JJ, Postma D, Koppelman GH, Smit HA, Söderhäll C, Chawes B, Kreiner-Møller E, Bisgaard H, Melén E, Boomsma DI, Custovic A, Jacobsson B, Probst-Hensch NM, Palmer LJ, Glass D, Hakonarson H, Melbye M, Jarvis DL, Jaddoe VW, Gieger C, Strachan DP, Martin NG, Jarvelin MR, Heinrich J, Evans DM, and Weidinger S

Subjects
Cell Differentiation genetics, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 20 genetics, Chromosomes, Human, Pair 5, Cytokines genetics, DNA-Binding Proteins genetics, Dermatitis, Atopic immunology, Epidermis immunology, Female, Filaggrin Proteins, Genetic Predisposition to Disease, Humans, Intermediate Filament Proteins genetics, Kinesins genetics, Male, Polymorphism, Single Nucleotide, Risk, Transcription Factors genetics, Dermatitis, Atopic genetics, Genetic Loci, Genome-Wide Association Study
Abstract

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

Published
2011
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8. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.

Author

Soler Artigas M, Loth DW, Wain LV, Gharib SA, Obeidat M, Tang W, Zhai G, Zhao JH, Smith AV, Huffman JE, Albrecht E, Jackson CM, Evans DM, Cadby G, Fornage M, Manichaikul A, Lopez LM, Johnson T, Aldrich MC, Aspelund T, Barroso I, Campbell H, Cassano PA, Couper DJ, Eiriksdottir G, Franceschini N, Garcia M, Gieger C, Gislason GK, Grkovic I, Hammond CJ, Hancock DB, Harris TB, Ramasamy A, Heckbert SR, Heliövaara M, Homuth G, Hysi PG, James AL, Jankovic S, Joubert BR, Karrasch S, Klopp N, Koch B, Kritchevsky SB, Launer LJ, Liu Y, Loehr LR, Lohman K, Loos RJ, Lumley T, Al Balushi KA, Ang WQ, Barr RG, Beilby J, Blakey JD, Boban M, Boraska V, Brisman J, Britton JR, Brusselle GG, Cooper C, Curjuric I, Dahgam S, Deary IJ, Ebrahim S, Eijgelsheim M, Francks C, Gaysina D, Granell R, Gu X, Hankinson JL, Hardy R, Harris SE, Henderson J, Henry A, Hingorani AD, Hofman A, Holt PG, Hui J, Hunter ML, Imboden M, Jameson KA, Kerr SM, Kolcic I, Kronenberg F, Liu JZ, Marchini J, McKeever T, Morris AD, Olin AC, Porteous DJ, Postma DS, Rich SS, Ring SM, Rivadeneira F, Rochat T, Sayer AA, Sayers I, Sly PD, Smith GD, Sood A, Starr JM, Uitterlinden AG, Vonk JM, Wannamethee SG, Whincup PH, Wijmenga C, Williams OD, Wong A, Mangino M, Marciante KD, McArdle WL, Meibohm B, Morrison AC, North KE, Omenaas E, Palmer LJ, Pietiläinen KH, Pin I, Pola Sbreve Ek O, Pouta A, Psaty BM, Hartikainen AL, Rantanen T, Ripatti S, Rotter JI, Rudan I, Rudnicka AR, Schulz H, Shin SY, Spector TD, Surakka I, Vitart V, Völzke H, Wareham NJ, Warrington NM, Wichmann HE, Wild SH, Wilk JB, Wjst M, Wright AF, Zgaga L, Zemunik T, Pennell CE, Nyberg F, Kuh D, Holloway JW, Boezen HM, Lawlor DA, Morris RW, Probst-Hensch N, Kaprio J, Wilson JF, Hayward C, Kähönen M, Heinrich J, Musk AW, Jarvis DL, Gläser S, Järvelin MR, Ch Stricker BH, Elliott P, O'Connor GT, Strachan DP, London SJ, Hall IP, Gudnason V, and Tobin MD

Subjects
Child, Humans, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Disease, Chronic Obstructive physiopathology, White People, Genome-Wide Association Study, Respiratory Function Tests
Abstract

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Published
2011
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9. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.

Author

Elks CE, Perry JR, Sulem P, Chasman DI, Franceschini N, He C, Lunetta KL, Visser JA, Byrne EM, Cousminer DL, Gudbjartsson DF, Esko T, Feenstra B, Hottenga JJ, Koller DL, Kutalik Z, Lin P, Mangino M, Marongiu M, McArdle PF, Smith AV, Stolk L, van Wingerden SH, Zhao JH, Albrecht E, Corre T, Ingelsson E, Hayward C, Magnusson PK, Smith EN, Ulivi S, Warrington NM, Zgaga L, Alavere H, Amin N, Aspelund T, Bandinelli S, Barroso I, Berenson GS, Bergmann S, Blackburn H, Boerwinkle E, Buring JE, Busonero F, Campbell H, Chanock SJ, Chen W, Cornelis MC, Couper D, Coviello AD, d'Adamo P, de Faire U, de Geus EJ, Deloukas P, Döring A, Smith GD, Easton DF, Eiriksdottir G, Emilsson V, Eriksson J, Ferrucci L, Folsom AR, Foroud T, Garcia M, Gasparini P, Geller F, Gieger C, Gudnason V, Hall P, Hankinson SE, Ferreli L, Heath AC, Hernandez DG, Hofman A, Hu FB, Illig T, Järvelin MR, Johnson AD, Karasik D, Khaw KT, Kiel DP, Kilpeläinen TO, Kolcic I, Kraft P, Launer LJ, Laven JS, Li S, Liu J, Levy D, Martin NG, McArdle WL, Melbye M, Mooser V, Murray JC, Murray SS, Nalls MA, Navarro P, Nelis M, Ness AR, Northstone K, Oostra BA, Peacock M, Palmer LJ, Palotie A, Paré G, Parker AN, Pedersen NL, Peltonen L, Pennell CE, Pharoah P, Polasek O, Plump AS, Pouta A, Porcu E, Rafnar T, Rice JP, Ring SM, Rivadeneira F, Rudan I, Sala C, Salomaa V, Sanna S, Schlessinger D, Schork NJ, Scuteri A, Segrè AV, Shuldiner AR, Soranzo N, Sovio U, Srinivasan SR, Strachan DP, Tammesoo ML, Tikkanen E, Toniolo D, Tsui K, Tryggvadottir L, Tyrer J, Uda M, van Dam RM, van Meurs JB, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Weedon MN, Wichmann HE, Willemsen G, Wilson JF, Wright AF, Young L, Zhai G, Zhuang WV, Bierut LJ, Boomsma DI, Boyd HA, Crisponi L, Demerath EW, van Duijn CM, Econs MJ, Harris TB, Hunter DJ, Loos RJ, Metspalu A, Montgomery GW, Ridker PM, Spector TD, Streeten EA, Stefansson K, Thorsteinsdottir U, Uitterlinden AG, Widen E, Murabito JM, Ong KK, and Murray A

Subjects
Adolescent, Body Height genetics, Body Size genetics, Child, DNA Copy Number Variations genetics, Female, Genetic Predisposition to Disease, Humans, Inheritance Patterns genetics, Obesity genetics, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, Reproducibility of Results, Time Factors, Aging physiology, Genetic Loci genetics, Genome-Wide Association Study, Menarche genetics
Abstract

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

Published
2010
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10. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.

Author

Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, Berry DJ, Warrington NM, Widen E, Hottenga JJ, Kaakinen M, Lange LA, Bradfield JP, Kerkhof M, Marsh JA, Mägi R, Chen CM, Lyon HN, Kirin M, Adair LS, Aulchenko YS, Bennett AJ, Borja JB, Bouatia-Naji N, Charoen P, Coin LJ, Cousminer DL, de Geus EJ, Deloukas P, Elliott P, Evans DM, Froguel P, Glaser B, Groves CJ, Hartikainen AL, Hassanali N, Hirschhorn JN, Hofman A, Holly JM, Hyppönen E, Kanoni S, Knight BA, Laitinen J, Lindgren CM, McArdle WL, O'Reilly PF, Pennell CE, Postma DS, Pouta A, Ramasamy A, Rayner NW, Ring SM, Rivadeneira F, Shields BM, Strachan DP, Surakka I, Taanila A, Tiesler C, Uitterlinden AG, van Duijn CM, Wijga AH, Willemsen G, Zhang H, Zhao J, Wilson JF, Steegers EA, Hattersley AT, Eriksson JG, Peltonen L, Mohlke KL, Grant SF, Hakonarson H, Koppelman GH, Dedoussis GV, Heinrich J, Gillman MW, Palmer LJ, Frayling TM, Boomsma DI, Davey Smith G, Power C, Jaddoe VW, Jarvelin MR, and McCarthy MI

Subjects
Alleles, Birth Weight, Cohort Studies, Diabetes Mellitus, Type 2 genetics, Ethnicity, Female, Genetic Predisposition to Disease, Genotype, Glucose metabolism, Humans, Male, Models, Genetic, Pregnancy, Adenylyl Cyclases genetics, Cyclins genetics, Isoenzymes genetics
Abstract

To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.

Published
2010
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11. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.

Author

Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H, Williams C, Hui J, Beilby J, Warrington NM, James A, Palmer LJ, Koppelman GH, Heinzmann A, Krueger M, Boezen HM, Wheatley A, Altmuller J, Shin HD, Uh ST, Cheong HS, Jonsdottir B, Gislason D, Park CS, Rasmussen LM, Porsbjerg C, Hansen JW, Backer V, Werge T, Janson C, Jönsson UB, Ng MC, Chan J, So WY, Ma R, Shah SH, Granger CB, Quyyumi AA, Levey AI, Vaccarino V, Reilly MP, Rader DJ, Williams MJ, van Rij AM, Jones GT, Trabetti E, Malerba G, Pignatti PF, Boner A, Pescollderungg L, Girelli D, Olivieri O, Martinelli N, Ludviksson BR, Ludviksdottir D, Eyjolfsson GI, Arnar D, Thorgeirsson G, Deichmann K, Thompson PJ, Wjst M, Hall IP, Postma DS, Gislason T, Gulcher J, Kong A, Jonsdottir I, Thorsteinsdottir U, and Stefansson K

Subjects
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport genetics, Algorithms, Asthma immunology, Asthma pathology, Case-Control Studies, Eosinophils pathology, Eye Proteins genetics, Genes, myb physiology, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Iceland, Interleukin-1 Receptor-Like 1 Protein, Interleukin-33, Interleukins genetics, Intracellular Signaling Peptides and Proteins, Leukocyte Count, Myocardial Infarction immunology, Myocardial Infarction pathology, Proteins genetics, Receptors, Cell Surface genetics, Asthma genetics, Eosinophils cytology, Myocardial Infarction genetics, Polymorphism, Single Nucleotide physiology
Abstract

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Published
2009
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