Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank

Hout, Cristopher V. Van; Tachmazidou, Ioanna; Backman, Joshua; Hoffman, Joshua X.; Ye, Bin; Pandey, Ashutosh Kumar; Gonzaga‐Jauregui, Claudia; Khalid, Shareef; Liu, Daren; Banerjee, Nilanjana; Li, Alexander H.; Ó'Dúshláine, Colm; Marcketta, Anthony; Staples, Jeffrey; Schurmann, Claudia; Hawes, Alicia; Maxwell, Evan K.; Barnard, Leland; Lopez, Alexander; Penn, John S.; Habegger, Lukas; Blumenfeld, Andrew; Yadav, Ashish; Praveen, Kavita; Jones, Marcus B.; Salerno, William; Chung, Wendy K.; Surakka, Ida; Willer, Cristen J.; Hveem, Kristian; Leader, Joseph B.; Carey, David J.; Ledbetter, David H.; Cardon, Lon R.; Yancopouloš, George D.; Economides, Aris N.; Coppola, Giovanni; Shuldiner, Alan R.; Balasubramanian, Suganthi; Cantor, Michael; Nelson, Matthew R.; Whittaker, John C.; Reid, Jeffrey G.; Marchini, Jonathan; Overton, John D.; Scott, Robert A.; Abecasis, Gonçalo R.; Yerges‐Armstrong, Laura M.; Baras, Aris

doi:10.1101/572347

Cited by 111 publications

(169 citation statements)

References 52 publications

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“…Sixth, PolyFun (and SuSiE) were designed for quantitative phenotypes but can also be applied to binary phenotypes; alternative methods designed for binary phenotypes may further increase power. Seventh, we restricted our analyses to MAF>0.001 SNPs, because SNPs with lower MAFs are often not well-imputed 62 . Future studies with whole genome sequencing data could potentially fine-map MAF≤0.001 SNPs, but the performance of PolyFun + SuSiE on sequencing data has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Functionally-informed fine-mapping and polygenic localization of complex trait heritability

Weissbrod

Hormozdiari

Benner

et al. 2019

Preprint

162

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Fine-mapping aims to identify causal variants impacting complex traits. Several recent methods improve fine-mapping accuracy by prioritizing variants in enriched functional annotations. However, these methods can only use information at genome-wide significant loci (and/or a small number of functional annotations), severely limiting the benefit of functional data. We propose PolyFun, a computationally scalable framework to improve fine-mapping accuracy using genome-wide functional data for a broad set of coding, conserved, regulatory and LD-related annotations. PolyFun prioritizes variants in enriched functional annotations by specifying prior causal probabilities for fine-mapping methods such as SuSiE or FINEMAP, employing special procedures to ensure robustness to model misspecification and winner's curse. In simulations, PolyFun + SuSiE and PolyFun + FINEMAP were well-calibrated and identified >20% more variants with posterior causal probability >0.95 than their non-functionally informed counterparts (and >33% more fine-mapped variants than previous functionally-informed fine-mapping methods). In analyses of 47 UK Biobank traits (average N=317K), PolyFun + SuSiE identified 3,025 fine-mapped varianttrait pairs with posterior causal probability >0.95, a >32% improvement vs. SuSiE; 223 variants were finemapped for multiple genetically uncorrelated traits, indicating pervasive pleiotropy. We used posterior mean per-SNP heritabilities from PolyFun + SuSiE to perform polygenic localization, constructing minimal sets of common SNPs causally explaining 50% of common SNP heritability; these sets ranged in size from 25 (hair color) to 3,400 (height) to 550,000 (chronotype). In conclusion, PolyFun prioritizes variants for functional follow-up and provides insights into complex trait architectures.

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Section: Discussionmentioning

confidence: 99%

Functionally-informed fine-mapping and polygenic localization of complex trait heritability

Weissbrod

Hormozdiari

Benner

et al. 2019

Preprint

162

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“…The UK Biobank (UKB) is a large cohort study consists of approximately half a million participants aged between 40 and 69 at recruitment, with extensive phenotypic records 18 65 and Functionally Equivalent (FE) 66 .…”

Section: Uk Biobank Datamentioning

confidence: 99%

“…Genotyped/imputed data were filtered with standard QC criteria in PLINK2 20 , e.g., MAF ≥ 0.01, Hardy-Weinberg Equilibrium test P ≥ 10 -6 , genotyping rate ≥ 0.95, and imputation info score ≥ 0.8 in real data analyses. In addition, the UKB released its first tranche of whole-exome sequence (WES) data of 49,960 participants in March 201965 . The WES variants had been called and cleaned by two different pipelines, Regeneron's Seal Point Balinese (SPB)…”

mentioning

confidence: 99%

A resource-efficient tool for mixed model association analysis of large-scale data

Jiang

Zheng

et al. 2019

Preprint

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The genome-wide association study (GWAS) has been widely used as an experimental design to detect associations between genetic variants and a phenotype. Two major confounding factors, population stratification and relatedness, could potentially lead to inflated GWAS test-statistics and thereby spurious associations. Mixed linear model (MLM)-based approaches can be used to account for sample structure. However, genome-wide association (GWA) analyses in biobank samples such as the UK Biobank (UKB) often exceed the capability of most existing MLM-based tools especially if the number of traits is large. Here, we developed an MLM-based tool (called fastGWA) that controls for population stratification by principal components and relatedness by a sparse genetic relationship matrix for GWA analyses of biobank-scale data. We demonstrated by extensive simulations that fastGWA is reliable, robust and highly resource-efficient. We then applied fastGWA to 2,173 traits on 456,422 array-genotyped and imputed individuals and 2,048 traits on 46,191 whole-exome-sequenced individuals in the UKB.

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“…We identified LRRK2 pLoF variants, and assessed the associated phenotypic changes, in three large cohorts of genetically characterized individuals. Firstly, we annotated LRRK2 pLoF variants in two large sequencing cohorts: the gnomAD v2.1.1 dataset, which contains 125,748 exomes and 15,708 genomes from unrelated individuals 9 , and the 46,062 exome-sequenced unrelated European individuals from the UK Biobank 33 . We identified 633 individuals in gnomAD and 258 individuals in the UK Biobank with 150 unique candidate LRRK2 LoF variants, a combined carrier frequency of 0.48%.…”

Section: Main Textmentioning

confidence: 99%

“…We identified all individuals with putative LoF variants detected in the FE analysis pipeline using GATK 3.0 for variant calling and filtering 33 . We did not use the SPB pipeline calls due to advertised errors in the Regeneron Genetics Center pipeline at the time we were conducting these analyses.…”

Section: Uk Biobank Variant Detection and Curationmentioning

confidence: 99%

Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson’s disease

Whiffin

Armean

Kleinman

et al. 2019

Preprint

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Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation, and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes 1,2 . Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease 3,4 , suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns 5-8 , the biological consequences of LRRK2 inhibition have not been wellcharacterized in humans. Here we systematically analyse pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD) 9 , 49,960 exome sequenced individuals from the UK Biobank, and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2, 82.5% with experimental validation. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but are not strongly associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that partially downregulate LRRK2 levels or kinase activity are unlikely to have major on-target safety liabilities. Our results demonstrate the value of largescale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.

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Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank

Cited by 111 publications

References 52 publications

Functionally-informed fine-mapping and polygenic localization of complex trait heritability

Functionally-informed fine-mapping and polygenic localization of complex trait heritability

A resource-efficient tool for mixed model association analysis of large-scale data

Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson’s disease

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