EGAGenomicsIllumina HiSeq 2000, Illumina HiSeq 2000 (ILLUMINA)Whole Genome Sequencinghttps://ega-archive.org/studies/EGAS00001000090EGAEGA study EGAS00001000090UK10K_COHORT_ALSPAC REL-2012-06-02: Phenotype dataUK10K_COHORT_ALSPAC REL-2011-12-01UK10K_COHORT_ALSPAC REL-2012-06-02restrictedEGAGenome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm.So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10(-9)) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10(-8)), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10(-11)), 12q21.2 (rs12230172, P=7.53 × 10(-11)) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10(-9)). Our findings provide further insights into the genetic basis of the different glioma subtypes.Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies, but the generalizability of such findings remains unknown. Here we genotype 1,267 individuals from a Greek population isolate on the Illumina HumanExome Beadchip, in search of functional coding variants associated with lipids traits. We find genome-wide significant evidence for association between R19X, a functional variant in APOC3, with increased high-density lipoprotein and decreased triglycerides levels. Approximately 3.8% of individuals are heterozygous for this cardioprotective variant, which was previously thought to be private to the Amish founder population. R19X is rare (<0.05% frequency) in outbred European populations. The increased frequency of R19X enables discovery of this lipid traits signal at genome-wide significance in a small sample size. This work exemplifies the value of isolated populations in successfully detecting transferable rare variant associations of high medical relevance.Genome-wide association study identifies multiple susceptibility loci for glioma.Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer.A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates.The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A.Henrion Marc Y R MY, Purdue Mark P MP, Scelo Ghislaine G, Broderick Peter P, Frampton Matthew M, Ritchie Alastair A, Meade Angela A, Li Peng P, McKay James J, Johansson Mattias M, Lathrop Mark M, Larkin James J, Rothman Nathaniel N, Wang Zhaoming Z, Chow Wong-Ho WH, Stevens Victoria L VL, Diver W Ryan WR, Albanes Demetrius D, Virtamo Jarmo J, Brennan Paul P, Eisen Timothy T, Chanock Stephen S, Houlston Richard S RSKinnersley Ben B, Labussière Marianne M, Holroyd Amy A, Di Stefano Anna-Luisa AL, Broderick Peter P, Vijayakrishnan Jayaram J, Mokhtari Karima K, Delattre Jean-Yves JY, Gousias Konstantinos K, Schramm Johannes J, Schoemaker Minouk J MJ, Fleming Sarah J SJ, Herms Stefan S, Heilmann Stefanie S, Schreiber Stefan S, Wichmann Heinz-Erich HE, Nöthen Markus M MM, Swerdlow Anthony A, Lathrop Mark M, Simon Matthias M, Bondy Melissa M, Sanson Marc M, Houlston Richard S RSTachmazidou Ioanna I, Dedoussis George G, Southam Lorraine L, Farmaki Aliki-Eleni AE, Ritchie Graham R S GR, Xifara Dionysia K DK, Matchan Angela A, Hatzikotoulas Konstantinos K, Rayner Nigel W NW, Chen Yuan Y, Pollin Toni I TI, O'Connell Jeffrey R JR, Yerges-Armstrong Laura M LM, Kiagiadaki Chrysoula C, Panoutsopoulou Kalliope K, Schwartzentruber Jeremy J, Moutsianas Loukas L, Tsafantakis Emmanouil E, Tyler-Smith Chris C, McVean Gil G, Xue Yali Y, Zeggini Eleftheria EVijayakrishnan Jayaram J, Henrion Marc M, Moorman Anthony V AV, Fiege Bettina B, Kumar Rajiv R, da Silva Filho Miguel Inacio MI, Holroyd Amy A, Koehler Rolf R, Thomsen Hauke H, Irving Julie A JA, Allan James M JM, Lightfoot Tracy T, Roman Eve E, Kinsey Sally E SE, Sheridan Eamonn E, Thompson Pamela D PD, Hoffmann Per P, Nöthen Markus M MM, Mühleisen Thomas W TW, Eisele Lewin L, Bartram Claus R CR, Schrappe Martin M, Greaves Mel M, Hemminki Kari K, Harrison Christine J CJ, Stanulla Martin M, Houlston Richard S RSfalseUK10K COHORT ALSPACThe UK10K project proposes a series of complementary genetic approaches to find new low-frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome-wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein-coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will directly analyse quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Avon Longitudinal Study of Parents and Children (ALSPAC) is a two-generation prospective study. Pregnant women living in one of three health districts in the former county of Avon with an expected delivery date between April 1991 and December 1992 were eligible to be enrolled in the study, and this formed the initial point of contact for the development of a large, family based resource. Information has been collected on the children and the mothers through retrieval of biological materials (e.g. antenatal blood samples, placentas), biological sampling (e.g. collection of cord blood, umbilical cord, milk teeth, hair, toenails, blood and urine), self-administered questionnaires, data extraction from medical notes, linkage to routine information systems and at repeat research clinics.2021-04-23 20:10:07EGAS00001000090960624343240264636722582661926424050EGAD00001000195EGAD00001000789EGAD00001000740EGAC00001000205