Whole-genome sequence based association studies of complex traits: the UK10K project. N. Timpson, UK10K Consortium: Cohorts MRC/UoB IEU/SSCM, Bristol Univ, Bristol, United Kingdom.

   The UK10K project (www.uk10k.org) is a collaborative effort between multiple research centres mainly in the UK which has four core aims: uncover genetic variants of a broad frequency range, generate comprehensive reference panels for imputation of genetic variation out into larger collections, perform association analyses in an extensive list of phenotypes and lastly to provide a sequence and phenotype based resource for the research community. As part of Cohorts component of the UK10K project, 4,000 individuals from two deeply phenotyped cohorts - TwinsUK and the Avon Longitudinal Study of Parents and Children (ALSPAC) - have been sequenced to 6x coverage using next-generation sequencing technology. The data generated has been used to explore phenotypic associations in over 50 cardiometabolic and health related traits using both single point common variant and burden based rare variant tests. These have indicated novel trait associations in a series of contexts; new variants in known gene regions, new associations in novel gene regions, association in previously poorly imputed regions and rarer variation based associations. Initial results indicate that a number of these appear to replicate in the full ALSPAC data set and further analyses are allowing us to address a range of related questions related to the performance and utility of whole-genome sequencing. Examples of these questions are: (i) To what extent rare variants contribute to phenotypic variance in complex traits; (ii) To what extent does the presence of structure within phenotype and genotype data complicate the interpretation of association signals at differing allele frequencies; (iii) To what extent is there an over-representation of functionally annotated genomic regions within loci harboring association signal. A panel of approximately 50 cardiometabolic quantitative traits is analyzed in conjunction with whole-genome sequence data to address these questions, and initial association results will also be presented. In summary, the data provide insights about what large-scale whole-genome sequencing efforts are likely to reveal for the genetic architecture of complex traits. All data, both phenotypic and genetic, generated by the project are being made available to the scientific community under managed access.

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