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Publications by Year: 2010

2010

Raychaudhuri S, Korn J, McCarroll S, International Schizophrenia Consortium, Altshuler D, Sklar P, Purcell S, Daly M. Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet. 2010;6(9):e1001097.
Publisher's Version
Publisher's Version
Investigators have linked rare copy number variation (CNVs) to neuropsychiatric diseases, such as schizophrenia. One hypothesis is that CNV events cause disease by affecting genes with specific brain functions. Under these circumstances, we expect that CNV events in cases should impact brain-function genes more frequently than those events in controls. Previous publications have applied "pathway" analyses to genes within neuropsychiatric case CNVs to show enrichment for brain-functions. While such analyses have been suggestive, they often have not rigorously compared the rates of CNVs impacting genes with brain function in cases to controls, and therefore do not address important confounders such as the large size of brain genes and overall differences in rates and sizes of CNVs. To demonstrate the potential impact of confounders, we genotyped rare CNV events in 2,415 unaffected controls with Affymetrix 6.0; we then applied standard pathway analyses using four sets of brain-function genes and observed an apparently highly significant enrichment for each set. The enrichment is simply driven by the large size of brain-function genes. Instead, we propose a case-control statistical test, cnv-enrichment-test, to compare the rate of CNVs impacting specific gene sets in cases versus controls. With simulations, we demonstrate that cnv-enrichment-test is robust to case-control differences in CNV size, CNV rate, and systematic differences in gene size. Finally, we apply cnv-enrichment-test to rare CNV events published by the International Schizophrenia Consortium (ISC). This approach reveals nominal evidence of case-association in neuronal-activity and the learning gene sets, but not the other two examined gene sets. The neuronal-activity genes have been associated in a separate set of schizophrenia cases and controls; however, testing in independent samples is necessary to definitively confirm this association. Our method is implemented in the PLINK software package.
Lango Allen H, Estrada K, Lettre G, Berndt S, Weedon M, Rivadeneira F, Willer C, Jackson A, Vedantam S, Raychaudhuri S, Ferreira T, Wood A, Weyant R, Segrè A, Speliotes E, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa N, Randall J, Qi L, Smith AV, Mägi R, Pastinen T, Liang L, Heid I, Luan J, Thorleifsson G, Winkler T, Goddard M, Sin Lo K, Palmer C, Workalemahu T, Aulchenko Y, Johansson Å, Zillikens C, Feitosa M, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer N, Hayward C, Hottenga JJ, Jacobs K, Knowles J, Kutalik Z, Monda K, Polašek O, Preuss M, Rayner N, Robertson N, Steinthorsdottir V, Tyrer J, Voight B, Wiklund F, Xu J, Zhao JH, Nyholt D, Pellikka N, Perola M, Perry J, Surakka I, Tammesoo ML, Altmaier E, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman D, Chen C, Coin L, Cooper M, Dixon A, Gibson Q, Grundberg E, Hao K, Juhani Junttila, Kaplan L, Kettunen J, König I, Kwan T, Lawrence R, Levinson D, Lorentzon M, McKnight B, Morris A, Müller M, Suh Ngwa J, Purcell S, Rafelt S, Salem R, Salvi E, Sanna S, Shi J, Sovio U, Thompson J, Turchin M, Vandenput L, Verlaan D, Vitart V, White C, Ziegler A, Almgren P, Balmforth A, Campbell H, Citterio L, De Grandi A, Dominiczak A, Duan J, Elliott P, Elosua R, Eriksson J, Freimer N, Geus E, Glorioso N, Haiqing S, Hartikainen AL, Havulinna A, Hicks A, Hui J, Igl W, Illig T, Jula A, Kajantie E, Kilpeläinen T, Koiranen M, Kolcic I, Koskinen S, Kovacs P, Laitinen J, Liu J, Lokki ML, Marusic A, Maschio A, Meitinger T, Mulas A, Paré G, Parker A, Peden J, Petersmann A, Pichler I, Pietiläinen K, Pouta A, Ridderstråle M, Rotter J, Sambrook J, Sanders A, Schmidt CO, Sinisalo J, Smit J, Stringham H, Bragi Walters, Widen E, Wild S, Willemsen G, Zagato L, Zgaga L, Zitting P, Alavere H, Farrall M, McArdle W, Nelis M, Peters M, Ripatti S, Meurs J, Aben K, Ardlie K, Beckmann J, Beilby J, Bergman R, Bergmann S, Collins F, Cusi D, Heijer M, Eiriksdottir G, Gejman P, Hall A, Hamsten A, Huikuri H, Iribarren C, Kähönen M, Kaprio J, Kathiresan S, Kiemeney L, Köcher T, Launer L, Lehtimäki T, Melander O, Mosley T, Musk A, Nieminen M, O’Donnell C, Ohlsson C, Oostra B, Palmer L, Raitakari O, Ridker P, Rioux J, Rissanen A, Rivolta C, Schunkert H, Shuldiner A, Siscovick D, Stumvoll M, Tönjes A, Tuomilehto J, Ommen GJ, Viikari J, Heath A, Martin N, Montgomery G, Province M, Kayser M, Arnold A, Atwood L, Boerwinkle E, Chanock S, Deloukas P, Gieger C, Gronberg H, Hall P, Hattersley A, Hengstenberg C, Hoffman W, Lathrop M, Salomaa V, Schreiber S, Uda M, Waterworth D, Wright A, Assimes T, Barroso I, Hofman A, Mohlke K, Boomsma D, Caulfield M, Cupples A, Erdmann J, Fox C, Gudnason V, Gyllensten U, Harris T, Hayes R, Jarvelin MR, Mooser V, Munroe P, Ouwehand W, Penninx B, Pramstaller P, Quertermous T, Rudan I, Samani N, Spector T, Völzke H, Watkins H, Wilson J, Groop L, Haritunians T, Hu F, Kaplan R, Metspalu A, North K, Schlessinger D, Wareham N, Hunter D, O’Connell J, Strachan D, Wichmann HE, Borecki I, Duijn C, Schadt E, Thorsteinsdottir U, Peltonen L, Uitterlinden A, Visscher P, Chatterjee N, Loos R, Boehnke M, McCarthy M, Ingelsson E, Lindgren C, Abecasis G, Stefansson K, Frayling T, Hirschhorn J. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010;467(7317):832–8.
Publisher's Version
Publisher's Version
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Speliotes E, Willer C, Berndt S, Monda K, Thorleifsson G, Jackson A, Lango Allen H, Lindgren C, Luan J, Mägi R, Randall J, Vedantam S, Winkler T, Qi L, Workalemahu T, Heid I, Steinthorsdottir V, Stringham H, Weedon M, Wheeler E, Wood A, Ferreira T, Weyant R, Segrè A, Estrada K, Liang L, Nemesh J, Park JH, Gustafsson S, Kilpeläinen T, Yang J, Bouatia-Naji N, Esko T, Feitosa M, Kutalik Z, Mangino M, Raychaudhuri S, Scherag A, Smith AV, Welch R, Zhao JH, Aben K, Absher D, Amin N, Dixon A, Fisher E, Glazer N, Goddard M, Heard-Costa N, Hoesel V, Hottenga JJ, Johansson Å, Johnson T, Ketkar S, Lamina C, Li S, Moffatt M, Myers R, Narisu N, Perry J, Peters M, Preuss M, Ripatti S, Rivadeneira F, Sandholt C, Scott L, Timpson N, Tyrer J, Wingerden S, Watanabe R, White C, Wiklund F, Barlassina C, Chasman D, Cooper M, Jansson JO, Lawrence R, Pellikka N, Prokopenko I, Shi J, Thiering E, Alavere H, Alibrandi M, Almgren P, Arnold A, Aspelund T, Atwood L, Balkau B, Balmforth A, Bennett A, Ben-Shlomo Y, Bergman R, Bergmann S, Biebermann H, Blakemore A, Boes T, Bonnycastle L, Bornstein S, Brown M, Buchanan T, Busonero F, Campbell H, Cappuccio F, Cavalcanti-Proença C, Chen YDI, Chen CM, Chines P, Clarke R, Coin L, Connell J, Day I, Heijer M, Duan J, Ebrahim S, Elliott P, Elosua R, Eiriksdottir G, Erdos M, Eriksson J, Facheris M, Felix S, Fischer-Posovszky P, Folsom A, Friedrich N, Freimer N, Fu M, Gaget S, Gejman P, Geus E, Gieger C, Gjesing A, Goel A, Goyette P, Grallert H, Grässler J, Greenawalt D, Groves C, Gudnason V, Guiducci C, Hartikainen AL, Hassanali N, Hall A, Havulinna A, Hayward C, Heath A, Hengstenberg C, Hicks A, Hinney A, Hofman A, Homuth G, Hui J, Igl W, Iribarren C, Isomaa B, Jacobs K, Jarick I, Jewell E, John U, Jørgensen T, Jousilahti P, Jula A, Kaakinen M, Kajantie E, Kaplan L, Kathiresan S, Kettunen J, Kinnunen L, Knowles J, Kolcic I, König I, Koskinen S, Kovacs P, Kuusisto J, Kraft P, Kvaløy K, Laitinen J, Lantieri O, Lanzani C, Launer L, Lecoeur C, Lehtimäki T, Lettre G, Liu J, Lokki ML, Lorentzon M, Luben R, Ludwig B, MAGIC, Manunta P, Marek D, Marre M, Martin N, McArdle W, McCarthy A, McKnight B, Meitinger T, Melander O, Meyre D, Midthjell K, Montgomery G, Morken M, Morris A, Mulic R, Ngwa J, Nelis M, Neville M, Nyholt D, O’Donnell C, O’Rahilly S, Ong K, Oostra B, Paré G, Parker A, Perola M, Pichler I, Pietiläinen K, Platou C, Polašek O, Pouta A, Rafelt S, Raitakari O, Rayner N, Ridderstråle M, Rief W, Ruokonen A, Robertson N, Rzehak P, Salomaa V, Sanders A, Sandhu M, Sanna S, Saramies J, Savolainen M, Scherag S, Schipf S, Schreiber S, Schunkert H, Silander K, Sinisalo J, Siscovick D, Smit J, Soranzo N, Sovio U, Stephens J, Surakka I, Swift A, Tammesoo ML, Tardif JC, Teder-Laving M, Teslovich T, Thompson J, Thomson B, Tönjes A, Tuomi T, Meurs J, Ommen GJ, Vatin V, Viikari J, Visvikis-Siest S, Vitart V, Vogel C, Voight B, Waite L, Wallaschofski H, Walters B, Widen E, Wiegand S, Wild S, Willemsen G, Witte D, Witteman J, Xu J, Zhang Q, Zgaga L, Ziegler A, Zitting P, Beilby J, Farooqi S, Hebebrand J, Huikuri H, James A, Kähönen M, Levinson D, Macciardi F, Nieminen M, Ohlsson C, Palmer L, Ridker P, Stumvoll M, Beckmann J, Boeing H, Boerwinkle E, Boomsma D, Caulfield M, Chanock S, Collins F, Cupples A, Smith GD, Erdmann J, Froguel P, Gronberg H, Gyllensten U, Hall P, Hansen T, Harris T, Hattersley A, Hayes R, Heinrich J, Hu F, Hveem K, Illig T, Jarvelin MR, Kaprio J, Karpe F, Khaw KT, Kiemeney L, Krude H, Laakso M, Lawlor D, Metspalu A, Munroe P, Ouwehand W, Pedersen O, Penninx B, Peters A, Pramstaller P, Quertermous T, Reinehr T, Rissanen A, Rudan I, Samani N, Schwarz P, Shuldiner A, Spector T, Tuomilehto J, Uda M, Uitterlinden A, Valle T, Wabitsch M, Waeber G, Wareham N, Watkins H, Procardis Consortium, Wilson J, Wright A, Zillikens C, Chatterjee N, McCarroll S, Purcell S, Schadt E, Visscher P, Assimes T, Borecki I, Deloukas P, Fox C, Groop L, Haritunians T, Hunter D, Kaplan R, Mohlke K, O’Connell J, Peltonen L, Schlessinger D, Strachan D, Duijn C, Wichmann HE, Frayling T, Thorsteinsdottir U, Abecasis G, Barroso I, Boehnke M, Stefansson K, North K, McCarthy M, Hirschhorn J, Ingelsson E, Loos R. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010;42(11):937–48.
Publisher's Version
Publisher's Version
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Franke A, McGovern D, Barrett J, Wang K, Radford-Smith G, Ahmad T, Lees C, Balschun T, Lee J, Roberts R, Anderson C, Bis J, Bumpstead S, Ellinghaus D, Festen E, Georges M, Green T, Haritunians T, Jostins L, Latiano A, Mathew C, Montgomery G, Prescott N, Raychaudhuri S, Rotter J, Schumm P, Sharma Y, Simms L, Taylor K, Whiteman D, Wijmenga C, Baldassano R, Barclay M, Bayless T, Brand S, Büning C, Cohen A, Colombel JF, Cottone M, Stronati L, Denson T, De Vos M, D’Inca R, Dubinsky M, Edwards C, Florin T, Franchimont D, Gearry R, Glas J, Van Gossum A, Guthery S, Halfvarson J, Verspaget H, Hugot JP, Karban A, Laukens D, Lawrance I, Lemann M, Levine A, Libioulle C, Louis E, Mowat C, Newman W, Panés J, Phillips A, Proctor D, Regueiro M, Russell R, Rutgeerts P, Sanderson J, Sans M, Seibold F, Steinhart H, Stokkers P, Torkvist L, Kullak-Ublick G, Wilson D, Walters T, Targan S, Brant S, Rioux J, D’Amato M, Weersma R, Kugathasan S, Griffiths A, Mansfield J, Vermeire S, Duerr R, Silverberg M, Satsangi J, Schreiber S, Cho J, Annese V, Hakonarson H, Daly M, Parkes M. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42(12):1118–25.
Publisher's Version
Publisher's Version
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
Beroukhim R, Mermel C, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm J, Dobson J, Urashima M, Mc Henry K, Pinchback R, Ligon A, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence M, Weir B, Tanaka K, Chiang D, Bass A, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye F, Sasaki H, Tepper J, Fletcher J, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin M, Jänne P, Daly M, Nucera C, Levine R, Ebert B, Gabriel S, Rustgi A, Antonescu C, Ladanyi M, Letai A, Garraway L, Loda M, Beer D, True L, Okamoto A, Pomeroy S, Singer S, Golub T, Lander E, Getz G, Sellers W, Meyerson M. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463(7283):899–905.
Publisher's Version
Publisher's Version
A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.
Neale B, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S, Tan P, Oh E, Merriam J, Souied E, Bernstein P, Li B, Frederick J, Zhang K, Brantley M, Lee A, Zack D, Campochiaro B, Campochiaro P, Ripke S, Smith T, Barile G, Katsanis N, Allikmets R, Daly M, Seddon J. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A. 2010;107(16):7395–400.
Publisher's Version
Publisher's Version

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.

Orozco G, Eyre S, Hinks A, Ke X, Consortium WTCCY, Wilson A, Bax D, Morgan A, Emery P, Steer S, Hocking L, Reid D, Wordsworth P, Harrison P, Thomson W, Barton A, Worthington J. Association of CD40 with rheumatoid arthritis confirmed in a large UK case-control study. Ann Rheum Dis. 2010;69(5):813–6.
Publisher's Version
Publisher's Version
OBJECTIVE: A recent meta-analysis of published genome-wide association studies (GWAS) in populations of European descent reported novel associations of markers mapping to the CD40, CCL21 and CDK6 genes with rheumatoid arthritis (RA) susceptibility while a large-scale, case-control association study in a Japanese population identified association with multiple single nucleotide polymorphisms (SNPs) in the CD244 gene. The aim of the current study was to validate these potential RA susceptibility markers in a UK population. METHODS: A total of 4 SNPs (rs4810485 in CD40, rs2812378 in CCL21, rs42041 in CDK6 and rs6682654 in CD244) were genotyped in a UK cohort comprising 3962 UK patients with RA and 3531 healthy controls using the Sequenom iPlex platform. Genotype counts in patients and controls were analysed with the chi(2) test using Stata. RESULTS: Association to the CD40 gene was robustly replicated (p=2 x 10(-4), OR 0.86, 95% CI 0.79 to 0.93) and modest evidence was found for association with the CCL21 locus (p=0.04, OR 1.08, 95% CI 1.01 to 1.16). However, there was no evidence for association of rs42041 (CDK6) and rs6682654 (CD244) with RA susceptibility in this UK population. Following a meta-analysis including the original data, association to CD40 was confirmed (p=7.8 x 10(-8), OR 0.87 (95% CI 0.83 to 0.92). CONCLUSION: In this large UK cohort, strong association of the CD40 gene with susceptibility to RA was found, and weaker evidence for association with RA in the CCL21 locus.
Karlson E, Chibnik L, Kraft P, Cui J, Keenan B, Ding B, Raychaudhuri S, Klareskog L, Alfredsson L, Plenge R. Cumulative association of 22 genetic variants with seropositive rheumatoid arthritis risk. Ann Rheum Dis. 2010;69(6):1077–85.
Publisher's Version
Publisher's Version
BACKGROUND: Recent discoveries of risk alleles have made it possible to define genetic risk profiles for patients with rheumatoid arthritis (RA). This study examined whether a cumulative score based on 22 validated genetic risk alleles for seropositive RA would identify high-risk, asymptomatic individuals who might benefit from preventive interventions. METHODS: Eight human leucocyte antigen (HLA) alleles and 14 single-nucleotide polymorphisms representing 13 validated RA risk loci were genotyped among 289 white seropositive cases and 481 controls from the US Nurses' Health Studies (NHS) and 629 white cyclic-citrullinated peptide antibody-positive cases and 623 controls from the Swedish Epidemiologic Investigation of Rheumatoid Arthritis (EIRA). A weighted genetic risk score (GRS) was created, in which the weight for each risk allele is the log of the published odds ratio (OR). Logistic regression was used to study associations with incident RA. Area under the curve (AUC) statistics were compared from a clinical-only model and clinical plus genetic model in each cohort. RESULTS: Patients with GRS >1.25 SD of the mean had a significantly higher OR of seropositive RA in both NHS (OR=2.9, 95%CI 1.8 to 4.6) and EIRA (OR 3.4, 95% CI 2.3 to 5.0) referent to the population average. In NHS, the AUC for a clinical model was 0.57 and for a clinical plus genetic model was 0.66, and in EIRA was 0.63 and 0.75, respectively. CONCLUSION: The combination of 22 risk alleles into a weighted GRS significantly stratifies individuals for RA risk beyond clinical risk factors alone. Given the low incidence of RA, the clinical utility of a weighted GRS is limited in the general population.
Voight B, Scott L, Steinthorsdottir V, Morris A, Dina C, Welch R, Zeggini E, Huth C, Aulchenko Y, Thorleifsson G, McCulloch L, Ferreira T, Grallert H, Amin N, Wu G, Willer C, Raychaudhuri S, McCarroll S, Langenberg C, Hofmann O, Dupuis J, Qi L, Segrè A, Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett A, Blagieva R, Boerwinkle E, Bonnycastle L, Bengtsson Boström K, Bravenboer B, Bumpstead S, Burtt N, Charpentier G, Chines P, Cornelis M, Couper D, Crawford G, Doney A, Elliott K, Elliott A, Erdos M, Fox C, Franklin C, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves C, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson A, Johnson P, Jørgensen T, Kao W, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren C, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken M, Narisu N, Nilsson P, Owen K, Payne F, Perry J, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner W, Robertson N, Rocheleau G, Roden M, Sampson M, Saxena R, Shields B, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham H, Sun Q, Swift A, Thorand B, Tichet J, Tuomi T, Dam R, Haeften T, Herpt T, Vliet-Ostaptchouk J, Walters B, Weedon M, Wijmenga C, Witteman J, Bergman R, Cauchi S, Collins F, Gloyn A, Gyllensten U, Hansen T, Hide W, Hitman G, Hofman A, Hunter D, Hveem K, Laakso M, Mohlke K, Morris A, Palmer C, Pramstaller P, Rudan I, Sijbrands E, Stein L, Tuomilehto J, Uitterlinden A, Walker M, Wareham N, Watanabe R, Abecasis G, Boehm B, Campbell H, Daly M, Hattersley A, Hu F, Meigs J, Pankow J, Pedersen O, Wichmann HE, Barroso I, Florez J, Frayling T, Groop L, Sladek R, Thorsteinsdottir U, Wilson J, Illig T, Froguel P, Duijn C, Stefansson K, Altshuler D, Boehnke M, McCarthy M, MAGIC investigators, GIANT Consortium. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010;42(7):579–89.
Publisher's Version
Publisher's Version
By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.