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- Butler-Laporte, G, et al.
(författare)
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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
- 2022
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 18:11, s. e1010367-
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Tidskriftsartikel (refereegranskat)abstract
- Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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- Raemoe, JT, et al.
(författare)
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Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure
- 2023
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1, s. 157-
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Tidskriftsartikel (refereegranskat)abstract
- Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 3504 cases and 861,198 controls. We identify 23 novel risk loci (p < 5 × 10−8) and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7). We demonstrate developmental stage-dependent immunostaining patterns of MEPE and RUNX2 in mouse otic capsules. In most association loci, the nearest protein-coding genes are implicated in bone remodelling, mineralization or severe skeletal disorders. We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies.
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- Rämö, JT, et al.
(författare)
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Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure
- 2023
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1, s. 157-
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Tidskriftsartikel (refereegranskat)abstract
- Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 3504 cases and 861,198 controls. We identify 23 novel risk loci (p < 5 × 10−8) and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7). We demonstrate developmental stage-dependent immunostaining patterns of MEPE and RUNX2 in mouse otic capsules. In most association loci, the nearest protein-coding genes are implicated in bone remodelling, mineralization or severe skeletal disorders. We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies.
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- Whiffin, N, et al.
(författare)
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The effect of LRRK2 loss-of-function variants in humans
- 2020
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:6, s. 869-877
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Tidskriftsartikel (refereegranskat)abstract
- 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 genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze 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. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
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- Karczewski, Konrad J., et al.
(författare)
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The mutational constraint spectrum quantified from variation in 141,456 humans
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 581, s. 434-443
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
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- Singer-Berk, Moriel, et al.
(författare)
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Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data
- 2023
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 110:9, s. 1496-1508
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Tidskriftsartikel (refereegranskat)abstract
- Predicted loss of function (pLoF) variants are often highly deleterious and play an important role in disease biology, but many pLoF variants may not result in loss of function (LoF). Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines’ PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 genes associated with autosomal-recessive disease from the Genome Aggregation Database (gnomAD v.2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in a low proportion expressed across transcripts (pext) scored region, or the presence of cryptic in-frame splice rescues. Variants predicted to evade LoF or to be potential artifacts were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of pLoF variants predicted as likely not LoF/not LoF, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.
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