Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes

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Science  01 Jun 2007:
Vol. 316, Issue 5829, pp. 1336-1341
DOI: 10.1126/science.1142364

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The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.

The pathophysiological basis of type 2 diabetes (T2D) remains unclear despite its growing global importance (1). Candidate gene and positional cloning efforts have suggested many putative susceptibility variants, but unequivocal replications are so far limited to variants in just three genes: PPARG, KCNJ11, and TCF7L2 (24).

Improved understanding of the correlation between genetic variants [linkage disequilibrium (LD)], allied to advances in genotyping technology, have enabled systematic searches for disease-associated common variants on a genome-wide scale. The Wellcome Trust Case Control Consortium (WTCCC) recently completed such a genome-wide association (GWA) scan in 1924 T2D cases and 2938 population controls from the United Kingdom, using the Affymetrix GeneChip Human Mapping 500 k Array Set (5). The strongest association signals genome-wide were observed for single-nucleotide polymorphisms (SNPs) in TCF7L2. [For example, for rs7901695, odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.25–1.49, and P = 6.7×10–13.] The other known T2D susceptibility variants were detected with effect sizes consistent with previous reports (2, 3).

Here, we describe how integration of data from the WTCCC scan and our own replication studies with similar information generated by the Diabetes Genetics Initiative (DGI) (6) and the Finland–United States Investigation of NIDDM Genetics (FUSION) (7) has identified several additional susceptibility variants for T2D.

In the WTCCC study, analysis of 490,032 autosomal SNPs in 16,179 samples yielded 459,448 SNPs that passed initial quality control (5). We considered only the 393,453 autosomal SNPs with minor allele frequency (MAF) exceeding 1% in both cases and controls and no extreme departure from Hardy-Weinberg equilibrium (P <10–4 in cases or controls) (8). This T2D-specific data set shows no evidence of substantial confounding from population substructure and genotyping biases (8).

To distinguish true associations from those reflecting fluctuations under the null or residual errors arising from aberrant allele calling, we first submitted putative signals from the WTCCC study to additional quality control, including cluster-plot visualization and validation genotyping on a second platform (8). Next, we attempted replication of selected signals in up to 3757 additional cases and 5346 controls (replication sets RS1 to RS3). RS1 comprised 2022 cases and 2037 controls from the U.K. Type 2 Diabetes Genetics Consortium collection (UKT2DGC) (all from Tayside, Scotland). RS2 included 632 additional T2D cases and 1750 population controls from the Exeter Family Study of Child Health (EFSOCH). A subset of SNPs were typed in RS3, comprising a further 1103 cases and 1559 controls from the UKT2DGC (table S1).

The first wave of validated SNPs sent for replication was selected from the 30 SNPs, in nine distinct chromosomal regions (excluding TCF7L2), which had, in the WTCCC scan alone, attained the most extreme (P <10–5) significance values on Cochran-Armitage tests of association. Genotyping of 21 representative SNPs generated evidence of replication (P < 0.05) for three of these nine regions (Table 1 and table S2).

Table 1.

Confirmed T2D susceptibility variants. Representative SNPs are shown for each signal with ORs and 95% CIs reported (for the Cochran-Armitage 1 df test) with respect to the risk allele (denoted in bold, with the ancestral allele underlined where known). SNPs selected for inclusion are those with the strongest evidence for association in the U.K. data sets (except in the case of TCF7L2, where, to maximize consistency across the data sets, rs7901695 is presented). In the case of HHEX, the U.K. meta-analysis combines data from rs5015480 and rs1111875 (r2 = 1 in HapMap CEU). Because DGI and FUSION had not typed the identical SNPs in all samples, results shown for those studies feature the SNP generating the strongest association: In all cases, these were SNPs in strong LD (minimum r2 0.95, except TCF7L2) and with consistent direction of effect with the SNP reported in the U.K. data (see table S3 for details). The use of different SNPs may result in slightly different estimates of P values and OR between the three studies. Combined estimates of the ORs were calculated by weighting the logORs of each study by the inverse of their variance.

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Rs8050136 [mapping to the FTO (fat mass and obesity-associated) gene region on chr16] was among a cluster of SNPs generating the strongest evidence for association outside TCF7L2 in the original scan [risk allele OR = 1.27 (1.16–1.37), P = 2.0 × 10–8] (fig. S1). This SNP showed strong replication [OR = 1.22 (1.12–1.32), P = 5.4 × 10–7]. As we recently reported (9), this effect on T2D risk is mediated through a primary effect on adiposity, and adjustment for body mass index (BMI) abolishes the T2D association.

Replication was also obtained for SNPs within the CDKAL1 locus on chromosome 6, including rs9465871 and rs10946398. Although rs9465871 generated the stronger signal in the WTCCC scan, replication at this SNP was modest (P = 0.023). The replication signal at rs10946398 was more striking [OR = 1.14 (1.07–1.22), P = 8.4 × 10–5] (Table 1 and table S2). Consistent evidence of association is provided by the DGI (P = 4.1 × 10–4 at rs7754840) and FUSION groups (P = 9.5 × 10–3 at rs471253) (Table 1 and table S3) (6, 7), both SNPs being strong (r2 > 0.99) proxies for rs10946398. Across all studies, combined evidence for association at CDKAL1 is compelling (P ∼4.1 ×10–11).

All associated SNPs map to a large (90 kb) intron within CDKAL1 (Fig. 1). Flanking recombination hotspots define a 200-kb interval likely to contain the etiological variant(s). CDKAL1 [cyclin-dependent kinase 5 (CDK5) regulatory subunit associated protein 1–like 1] encodes a 579-residue, 65-kD protein of unknown function. We have detected expression of CDKAL1 mRNA in human pancreatic islet and skeletal muscle (fig. S2). CDKAL1 shares considerable protein domain and amino acid homology with CDK5 regulatory subunit associated protein 1 (CDK5RAP1), a known inhibitor of CDK5 activation. CDK5 has been implicated in the regulation of pancreatic beta cell function through formation of p35/CDK5 complexes that down-regulate insulin expression (10, 11).

Fig. 1. (left)

Overview of CDKAL1 signal region. (A) Plot of –log (P values) for T2D (Cochran-Armitage test for trend) against chromosome position in Mb. Blue diamonds represent primary scan results and pink triangles denote meta-analysis results across all UK samples. (B) Genomic location of genes showing intron and exon structure (NCBI Build 35). Pink triangles show position of replication SNPs relative to gene structure. (C) MULTIZ (24) vertebrate alignment of 17 species showing evolutionary conservation. (D) GoldSurfer2 (25) plot of linkage disequilibrium (r2) for SNPs genotyped in WTCCC scan (passing T2D-specific quality control) in WTCCC T2D cases. (E) Recombination rate given as cM/MB. Red boxes represent recombination hotspots (26). (F) GoldSurfer2 plot of linkage disequilibrium (r2) for all HapMap (haplotype map of the human genome) SNPs across the region (HapMap CEU data) (27). Fig. 2. (right) Overview of chr9 signal region. Panel layout as in Fig. 1.

The third replicated association maps to the HHEX (homeobox, hematopoietically expressed) gene region on chromosome 10. This gene showed strong association in the WTCCC scan [rs5015480: risk allele OR = 1.22 (CI, 1.12–1.33), P = 5.4 × 10–6] and is a powerful biological candidate (12, 13). We could not optimize a replication assay for rs5015480 but observed evidence for replication at a perfect proxy, rs1111875 [risk allele OR = 1.08 (CI, 1.01–1.15), P = 0.02] (Table 1, tables S2 and S3). Both DGI and FUSION studies showed modest but consistent association signals generating strong combined evidence (P ∼5.7×10–10) for a role in T2D susceptibility (Table 1 and table S3). A fourth genome-wide association scan, in French subjects, recently yielded independent evidence for a T2D signal in this region (14). The signal resides within an extended (295 kb) region of LD containing not only HHEX [highly expressed in fetal and adult pancreas (fig. S2)] but also the genes encoding kinesin-interacting factor (KIF11) and insulin-degrading enzyme (IDE) (fig. S3). IDE represents a second strong biological candidate given postulated effects on both insulin signaling and islet function and data from rodent models (1517).

Of the remaining regions selected in the first wave, none showed any evidence of replication in U.K. samples (table S2), and for none was there strong support from the DGI and FUSION scans.

The relatively strict thresholds imposed for SNP selection in the first wave (i.e., point-wise P <10–5) help to limit false discovery, but many genuine susceptibility variants will fail to reach them. We initiated a second wave of replication based around SNPs for whichthe WTCCC scan generated more modest evidence for association (Cochran-Armitage P ∼10–2 to 10–5). We prioritized the 5367 SNPs in this range using additional criteria: (i) evidence of association in DGI and FUSION (6, 7); (ii) presence of multiple, independent (r2 < 0.4) associations within the same locus; and (iii) biological candidacy (8, 18).

Analysis of the 56 SNPs, representing 49 putative signals, selected for this “second wave” of replication (table S4) yielded two further regions implicated in T2D susceptibility. A cluster of SNPs on chromosome 9 (represented by rs10811661) generated a promising signal in all three scans. Replication was observed in UK samples [rs10811661: OR = 1.18 (CI, 1.08–1.28), P = 1.7 × 10–4), as well as DGI (P = 2.2× 10–5) and FUSION follow-up studies (rs2383208, P = 9.7 × 10–3). A second signal from the WTCCC scan located ∼100 kb 5′ [rs564398, OR = 1.16 (CI, 1.07–1.27), P = 3.2 × 10–4], was weakly supported in the FUSION scan but not the DGI scan (Table 1 and table S3), and was replicated in the U.K. RS samples [OR = 1.12 (CI, 1.05–1.19), P = 8.6 ×10–4] (Table 1 and table S3).

These two association signals are separated by a recombination hotspot (D′ between rs10811661 and rs564398 is 0.057, r2 < 0.001) (Fig. 2). Across all studies, the combined evidence for association is stronger for the 3′ (P ∼7.8×10–15) than for the 5′ (P ∼1.2 ×10–7) peak (Table 1). The 3′ signal maps to sequence with no characterized genes, whereas the recombination interval enclosing the 5′ signal includes the full coding sequences of CDKN2B and CDKN2A (encoding p15INK4b and p16INK4a, respectively). CDKN2A is a known tumor suppressor and its product, p16INK4a, inhibits CDK4 (cyclin-dependent kinase 4), a powerful regulator of pancreatic beta cell replication (1921). Overexpression of Cdkn2a leads to decreased islet proliferation in aging mice (22). Cdkn2b overexpression is also causally related to islet hypoplasia and diabetes in murine models (23). Both CDKN2B and CDKN2A display high levels of expression in pancreatic islets and pituitary (fig. S2).

A fifth replicated association lies within the IGF2BP2 gene on chromosome 3. We observed some evidence of association for SNPs in this region in the WTCCC scan (5) [e.g., rs4402960: OR = 1.15 (CI, 1.05–1.25), P = 1.7 × 10–3]. Consistent associations in the DGI and FUSION scans (6, 7) and the biological candidacy of the gene [a known regulator of insulin-like growth factor 2 (IGF2) translation] prompted replication. We obtained only modest evidence for replication at rs4402960 [OR = 1.09 (CI, 1.01–1.16), P = 0.018] (Table 1 and table S4), but combined evidence across all studies (P ∼8.6 × 10–16) establishes this as a genuine T2D signal (Table 1 and table S3). The associated SNPs map to a 57-kb region spanning the promoter and first 2 exons of IGF2BP2 (fig. S4).

Most of the remaining 50 “second-wave” SNPs can be discounted as susceptibility variants based on their failure to replicate (table S4), although some merit further consideration. One such example is rs9369425, located 57-kb downstream of the VEGFA (vascular endothelial growth factor A) gene on chromosome 6 (fig. S5). Evidence for association in the WTCCC scan [OR = 1.16 (CI, 1.06–1.27), P = 8.6 × 10–4] is supported by nominal replication in U.K. samples [OR = 1.08 (CI, 1.01–1.15), P = 0.03] and by DGI scan results [1.17 (1.04–1.32), P = 4.4 × 10–3]. Although no signal is apparent in the FUSION study, this does not allow us to reject the association. For 80% power to detect an OR of 1.11 (α = 0.05), more than 3000 case-control pairs are needed.

In the French genome-wide scan (14), variants in both the HHEX and SLC30A8 genes were implicated in T2D susceptibility. Because the associated SNPs in SLC30A8 are poorly captured on the Affymetrix chip (r2 < 0.01), the WTCCC scan was not informative for this locus. However, we genotyped rs13266634 independently and obtained replication of the finding [risk allele OR = 1.12 (CI, 1.05–1.18), P = 7.0 × 10–5 in all UK data] and across all three studies (P ∼5.3 ×10–8) (Table 1 and table S4).

The present analysis has contributed to identification of several confirmed T2D susceptibility loci. One of these (FTO) exerts its primary effect on T2D risk through an impact on adiposity (9): None of the other signals was attenuated by adjustment for BMI or waist circumference (tables S5 to S7). One of the remaining four loci (HHEX/IDE) represents a strong replication of findings recently reported (14). The other three loci (near CDKAL1, IGF2BP2, and CDKN2A), all showing extensive replication across the three studies, represent previously unknown T2D susceptibility loci.

Across the four T2D scans completed (57, 14), TCF7L2 clearly emerges as the largest association signal. On current evidence, all other confirmed loci display more modest effect sizes (between 1.10 and 1.25 per allele). Extensive resequencing and fine-mapping will be required to define the full spectrum of etiological variation at each locus, and these may yet identify variants with greater impact. Our findings offer clear lessons for the design of future studies. Robust identification of variants with such effect sizes is only feasible with large-scale sample sets (13,965 individuals were typed in the present study). Further, the exchange of data between groups (providing data on up to 32,554 samples) was key to the rapid and unequivocal identification of the signals we report.

As a result of the four GWA studies reported to date (57, 14), the number of genuine, replicated T2D susceptibility signals has climbed from three to nine (adding HHEX/IDE, SLC30A8, CDKAL1, CDKN2A, IGF2BP2, and FTO). However, these loci explain only a small proportion of the observed familiality (the sibling relative risk, λs, attributable to all loci in the U.K. samples, is only ∼1.07). We expect additional loci to be revealed by further rounds of replication initiated by more systematic metaanalysis of these and other scans. Our study provides an important validation of the genome-wide indirect association mapping approach and a demonstration of the value of aggressive data-sharing efforts. It also generates insights into T2D pathogenesis, emphasizing the likely importance of pathways involved in pancreatic beta cell development, regeneration, and function. In-depth physiological and functional studies are now needed to establish the precise mechanisms involved.

Membership of Wellcome Trust Case Control Consortium Management committee: Paul R. Burton,1 David G. Clayton,2 Lon R. Cardon,3 Nick Craddock,4 Panos Deloukas,5 Audrey Duncanson,6 Dominic P. Kwiatkowski,3,5 Mark I. McCarthy,3,7 Willem H. Ouwehand,8,9 Nilesh J. Samani,10 John A. Todd,2 Peter Donnelly (Chair)11

Analysis committee: Jeffrey C. Barrett,3 Paul R. Burton,1 Dan Davison,11 Peter Donnelly,11 Doug Easton,12 David Evans,3 Hin-Tak Leung,2 Jonathan L. Marchini1,1 Andrew P. Morris,3 Chris C. A. Spencer,11 Martin D. Tobin,1 Lon R. Cardon (Co-chair),3 David G. Clayton (Co-chair)2

UK Blood Services and University of Cambridge controls: Antony P. Attwood,5,8 James P. Boorman,8,9 Barbara Cant,8 Ursula Everson,13 Judith M. Hussey,14 Jennifer D. Jolley,8 Alexandra S. Knight,8 Kerstin Koch,8 Elizabeth Meech,15 Sarah Nutland,2 Christopher V. Prowse,16 Helen E. Stevens,2 Niall C. Taylor,8 Graham R. Walters,17 Neil M. Walker,2 Nicholas A. Watkins,8,9 Thilo Winzer,8 John A. Todd,2 Willem H. Ouwehand8,9

1958 birth cohort controls: Richard W. Jones,18 Wendy L. McArdle,18 Susan M. Ring,18 David P. Strachan,19 Marcus Pembrey18,20

Bipolar disorder (Aberdeen): Gerome Breen,21 David St. Clair21(Birmingham): Sian Caesar,22 Katherine Gordon-Smith,22,23 Lisa Jones22(Cardiff): Christine Fraser,23 Elaine K. Green,23 Detelina Grozeva,23 Marian L. Hamshere,23 Peter A. Holmans,23 Ian R. Jones,23 George Kirov,23 Valentina Moskvina,23 Ivan Nikolov,23 Michael C. O'Donovan,23 Michael J. Owen,23 Nick Craddock23(London): David A. Collier,24 Amanda Elkin,24 Anne Farmer,24 Richard Williamson,24 Peter McGuffin24(Newcastle): Allan H. Young,25 I. Nicol Ferrier25

Coronary artery disease (Leeds): Stephen G. Ball,26 Anthony J. Balmforth,26 Jennifer H. Barrett,26 D. Timothy Bishop,26 Mark M. Iles,26 Azhar Maqbool,26 Nadira Yuldasheva,26 Alistair S. Hall26(Leicester): Peter S. Braund,10 Paul R. Burton,1 Richard J. Dixon,10 Massimo Mangino,10 Suzanne Stevens,10 Martin D. Tobin,1 John R. Thompson,1 Nilesh J. Samani10

Crohn's disease (Cambridge): Francesca Bredin,27 Mark Tremelling,27 Miles Parkes,27(Edinburgh): Hazel Drummond,28 Charles W. Lees,28 Elaine R. Nimmo,28 Jack Satsangi28(London): Sheila A. Fisher,29 Alastair Forbes,30 Cathryn M. Lewis,29 Clive M. Onnie,29 Natalie J. Prescott,29 Jeremy Sanderson,31 Christopher G. Mathew29(Newcastle): Jamie Barbour,32 M. Khalid Mohiuddin,32 Catherine E. Todhunter,32 John C. Mansfield,32(Oxford): Tariq Ahmad,33 Fraser R. Cummings,33 Derek P. Jewell,33

Hypertension (Aberdeen): John Webster,34(Cambridge): Morris J. Brown,35 David G. Clayton2 (Evry, France): G. Mark Lathrop36(Glasgow): John Connell,37 Anna Dominiczak37(Leicester): Nilesh J. Samani10(London): Carolina A. Braga Marcano,38 Beverley Burke,38 Richard Dobson,38 Johannie Gungadoo,38 Kate L. Lee,38 Patricia B. Munroe,38 Stephen J. Newhouse,38 Abiodun Onipinla,38 Chris Wallace,38 Mingzhan Xue,38 Mark Caulfield,38(Oxford): Martin Farrall39

Rheumatoid arthritis: Anne Barton,40 The Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee,* Ian N. Bruce,40 Hannah Donovan,40 Steve Eyre,40 Paul D. Gilbert,40 Samantha L. Hider,40 Anne M. Hinks,40 Sally L. John,40 Catherine Potter,40 Alan J. Silman,40 Deborah P. M. Symmons,40 Wendy Thomson,40 Jane Worthington40

Type 1 diabetes: David G. Clayton,2 David B. Dunger,2,41 Sarah Nutland,2 Helen E. Stevens,2 Neil M. Walker,2 Barry Widmer,2,41 John A. Todd2

Type 2 diabetes (Exeter): Timothy M. Frayling,42,43 Rachel M. Freathy,42,43 Hana Lango,42,43 John R. B. Perry,42,43 Beverley M. Shields,43 Michael N. Weedon,42,43 Andrew T. Hattersley,42,43(London): Graham A. Hitman,44(Newcastle): Mark Walker45(Oxford): Kate S. Elliott,3,7 Christopher J. Groves,7 Cecilia M. Lindgren,3,7 Nigel W. Rayner,3,7 Nicholas J. Timpson,3,46 Eleftheria Zeggini,3,7 Mark I. McCarthy3,7

Tuberculosis (Gambia): Melanie Newport,47 Giorgio Sirugo,47(Oxford): Emily Lyons,3 Fredrik Vannberg,3 Adrian V. S. Hill3

Ankylosing spondylitis: Linda A. Bradbury,48 Claire Farrar,49 Jennifer J. Pointon,48 Paul Wordsworth,49 Matthew A. Brown48,49

Autoimmune thyroid disease: Jayne A. Franklyn,50 Joanne M. Heward,50 Matthew J. Simmonds,50 Stephen C. L. Gough50

Breast cancer: Sheila Seal,51 Breast Cancer Susceptibility Collaboration (UK),† Michael R. Stratton,51,52 Nazneen Rahman51

Multiple sclerosis: Maria Ban,53 An Goris,53 Stephen J. Sawcer,53 Alastair Compston53

Gambian controls (Gambia): David Conway,47 Muminatou Jallow,47 Melanie Newport,47 Giorgio Sirugo,47(Oxford): Kirk A. Rockett,3 Dominic P. Kwiatkowski3,5

DNA, genotyping, data QC, and informatics (Wellcome Trust Sanger Institute, Hinxton): Suzannah J. Bumpstead,5 Amy Chaney,5 Kate Downes,2,5 Mohammed J. R. Ghori,5 Rhian Gwilliam,5 Sarah E. Hunt,5 Michael Inouye,5 Andrew Keniry,5 Emma King,5 Ralph McGinnis,5 Simon Potter,5 Rathi Ravindrarajah,5 Pamela Whittaker,5 Claire Widden,5 David Withers,5 Panos Deloukas5(Cambridge): Hin-Tak Leung,2 Sarah Nutland,2 Helen E. Stevens,2 Neil M. Walker,2 John A. Todd2

Statistics (Cambridge): Doug Easton,12 David G. Clayton,2(Leicester): Paul R. Burton,1 Martin D. Tobin1(Oxford): Jeffrey C. Barrett,3 David Evans,3 Andrew P. Morris,3 Lon R. Cardon3(Oxford): Niall J. Cardin,11 Dan Davison,11 Teresa Ferreira,11 Joanne Pereira-Gale,11 Ingeleif B. Hallgrimsdóttir,11 Bryan N. Howie,11 Jonathan L. Marchini,11 Chris C. A. Spencer,11 Zhan Su,11 Yik Ying Teo,3,11 Damjan Vukcevic,11 Peter Donnelly11

Principal investigators: David Bentley,5‡ Matthew A. Brown,48,49 Lon R. Cardon,3 Mark Caulfield,38 David G. Clayton,2 Alistair Compston,53 Nick Craddock,23 Panos Deloukas,5 Peter Donnelly,11 Martin Farrall,39 Stephen C. L. Gough,50 Alistair S. Hall,26 Andrew T. Hattersley,42,43 Adrian V. S. Hill,3 Dominic P. Kwiatkowski,3,5 Christopher G. Mathew,29 Mark I. McCarthy,3,7 Willem H. Ouwehand,8,9 Miles Parkes,27 Marcus Pembrey,18,20 Nazneen Rahman,51 Nilesh J. Samani,10 Michael R. Stratton,51,52 John A. Todd,2 Jane Worthington40

1Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Adrian Building, University Road, Leicester, LE1 7RH, UK. 2Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge, CB2 0XY, UK. 3The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. 4Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. 5The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. 6The Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK. 7Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK. 8Department of Haematology, University of Cambridge, Long Road, Cambridge, CB2 2PT, UK. 9National Health Service Blood and Transplant, Cambridge Centre, Long Road, Cambridge, CB2 2PT, UK. 10Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK. 11Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK. 12Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK. 13National Health Service Blood and Transplant, Sheffield Centre, Longley Lane, Sheffield S5 7JN, UK. 14National Health Service Blood and Transplant, Brentwood Centre, Crescent Drive, Brentwood, CM15 8DP, UK. 15The Welsh Blood Service, Ely Valley Road, Talbot Green, Pontyclun, CF72 9WB, UK. 16The Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh, EH17 7QT, UK. 17National Health Service Blood and Transplant, Southampton Centre, Coxford Road, Southampton, SO16 5AF, UK. 18Avon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol, BS8 1TQ, UK. 19Division of Community Health Services, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK. 20Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. 21University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK. 22Department of Psychiatry, Division of Neuroscience, Birmingham University, Birmingham, B15 2QZ, UK. 23Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. 24 Social, Genetic and Developmental Psychiatry Centre, The Institute of Psychiatry, King's College London, De Crespigny Park Denmark Hill London SE5 8AF, UK. 25School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK. 26Leeds Institute of Genetics, Health and Therapeutics, and Leeds Institute of Molecular Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, LS1 3EX, UK. 27Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK. 28Gastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU UK. 29Department of Medical & Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London, SE1 9RT, UK. 30Institute for Digestive Diseases, University College London Hospitals Trust, London, NW1 2BU, UK. 31Department of Gastroenterology, Guy's and St. Thomas' National Health Service Foundation Trust, London, SE1 7EH, UK. 32Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK. 33Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford, OX2 6HE, UK. 34Medicine and Therapeutics, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Grampian AB9 2ZB, UK. 35Clinical Pharmacology Unit and the Diabetes and Inflammation Laboratory, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK. 36Centre National de Genotypage, 2, Rue Gaston Cremieux, Evry, Paris 91057. 37British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK. 38Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine, Charterhouse Square, London EC1M 6BQ, UK. 39Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. 40arc Arthritis Research Campaign, Epidemiology Research Unit, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. 41Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK. 42Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU UK. 43Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DU UK. 44Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London, E1 1BB UK. 45Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. 46Medical Research Council Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Road, Bristol BS2 8PR, UK. 47Medical Research Council Laboratories, Fajara, The Gambia. 48Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland 4102, Australia. 49Botnar Research Centre, University of Oxford, Headington, Oxford OX3 7BN, UK. 50Department of Medicine, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. 51Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK. 52Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. 53Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.

*Members of the Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee are listed after the WTCCC list.

†Members of the Breast Cancer Susceptibility Collaboration (UK) are listed after the BRAGGS list.

‡Present address: Illumina Cambridge, Chesterford Research Park, Little Chesterford, Near Saffron Walden, Essex, CB10 1XL, UK.

Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee Anne Barton,1 John D Isaacs,2 Ann W Morgan,3 Gerry D. Wilson4

1arc Epidemiology Unit, University of Manchester, Oxford Road, Manchester, M13 9PT, UK. 2Department of Rheumatology, University of Newcastle-Upon-Tyne, Framlington Place, Newcastle-Upon-Tyne NE2 4HH, UK. 3Leeds Institute of Molecular Medicine, Section of Academic Unit of Musculoskeletal Disease Wellcome Trust Brenner Building, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. 4Genomic Medicine, The University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.

Breast Cancer Susceptibility Collaboration (UK)

A. Ardern-Jones,1 J. Berg,2 A. Brady,3 N. Bradshaw,4 C. Brewer,5 G. Brice,6 B. Bullman,7 J. Campbell,8 B. Castle,9 R. Cetnarsyj,8 C. Chapman,10 C. Chu,11 N. Coates,12 T. Cole,10 R. Davidson,4 A. Donaldson,13 H. Dorkins,3 F. Douglas,2 D. Eccles,9 R. Eeles,1 F. Elmslie,6 D. G. Evans,7 S. Goff,6 S. Goodman,5 D. Goudie,2 J. Gray,15 L. Greenhalgh,16 H. Gregory,17 S. V. Hodgson,6 T. Homfray,6 R. S. Houlston,1 L. Izatt,18 L. Jackson,18 L. Jeffers,19 V. Johnson-Roffey,12 F. Kavalier,18 C. Kirk,19 F. Lalloo,7 C. Langman,18 I. Locke,1 M. Longmuir,4 J. Mackay,20 A. Magee,19 S. Mansour,6 Z. Miedzybrodzka,17 J. Miller,11 P. Morrison,19 V. Murday,4 J. Paterson,21 G. Pichert,18 M. Porteous,8 N. Rahman,6 M. Rogers,15 S. Rowe,22 S. Shanley,1 A. Saggar,6 G. Scott,2 L. Side,23 L. Snadden,4 M. Steel,2 M. Thomas,5 S. Thomas,1

1Clinical Genetics Service, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK. 2Department of Clinical Genetics, Ninewells Hospital, Dundee, DD1 9SY, UK. 3Medical and Community Genetics, Kennedy-Galton Centre, Level 8V, Northwick Park and St. Mark's NHS Trust, Watford Rd, Harrow, HA1 3UJ, UK. 4Institute of Medical Genetics, Yorkhill NHS Trust, Dalnair Street, Glasgow, G3 8SJ, UK. 5Clinical Genetics Department, Royal Devon and Exeter Hospital (Heavitree), Gladstone Road, Exeter, EX1 2ED, UK. 6Department of Clinical Genetics, St. George's Hospital Medical School, Jenner Wing, Cranmer Terrace, London, SW17 0RE, UK. 7Department of Medical Genetics, St. Mary's Hospital, Hathersage Road, Manchester, M13 0JH, UK. 8South East of Scotland Clinical Genetics Service, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. 9Department of Medical Genetics, The Princess Anne Hospital, Coxford Road, Southampton, S016 5YA, UK. 10Clinical Genetics Unit, Birmingham Women's Hospital, Metchley Park Road, Edgbaston, Birmingham, B15 2TG, UK. 11Yorkshire Regional Genetic Service, Department of Clinical Genetics, Cancer Genetics Building, St. James University Hospital, Beckett Street, Leeds, LS9 7TF, UK. 12Department of Clinical Genetics, Leicester Royal Infirmary, Leicester, LE1 5WW, UK. 13Department of Clinical Genetics, St Michael's Hospital, Southwell Street, Bristol, BS2 8EG, UK. 14Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. 15Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK. 16Department of Clinical Genetics, Alder Hey Children's Hospital, Eaton Road, Liverpool L12 2AP, UK. 17Clinical Genetics Centre, Argyll House, Foresterhill, Aberdeen, AB25 2ZR, UK. 18Clinical Genetics, 7th Floor New Guy's House, Guy's Hospital, St. Thomas Street, London, SE1 9RT, UK. 19Clinical Genetics Service, Belfast City Hospital Trust, Belvoir Park Hospital, Lisburn Road, Belfast, BT9 7AB, UK. 20Clinical and Medical Genetics Unit, Institute of Child Health, 30 Guildford Street, London, WC1N 1EH, UK. 21Department of Clinical Genetics, Addenbrooke's NHS Trust, Box 134, Hills Road, Cambridge, CB2 2QQ, UK. 22Department of Clinical Genetics, Moston Lodge, Countess of Chester Hospital, Liverpool Road,Chester, CH2 1UL, UK. 23Department of Clinical Genetics, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.

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Materials and Methods

Figs. S1 to S8

Tables S1 to S10


References and Notes

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