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Oct 3, 2024 | 
broadinstitute.org | Ari Navetta |Benjamin M. Neale
The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome. Epilepsy is one of the most common neurological disorders.
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Oct 2, 2024 | 
biorxiv.org | Wenhan Lu |Siwei Chen |Danielle Posthuma |Benjamin M. Neale
AbstractGenome-wide association studies (GWAS) and rare-variant association studies (RVAS) have identified thousands of genes and variants that affect multiple phenotypes. Here, using rare variant association results from the UK Biobank (UKB) data, we identify pervasive gene-level pleiotropy across diverse phenotypic domains and highlight genes with apparent allelic series that provide additional association support through disease pathways.
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Aug 26, 2024 | 
nature.com | Kai Yuan |Antonio F Pardiñas |Mingrui Yu |Tzu-Ting Chen |Max Lam |Mark Daly | +5 more
AbstractGenome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestry has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries.
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Jul 3, 2024 | 
nature.com | Caitlin Carey |Robbee Wedow |Duncan Palmer |Masahiro Kanai |Konrad J Karczewski |Samuel Bryant | +6 more
AbstractData within biobanks capture broad yet detailed indices of human variation, but biobank-wide insights can be difficult to extract due to complexity and scale. Here, using large-scale factor analysis, we distill hundreds of variables (diagnoses, assessments and survey items) into 35 latent constructs, using data from unrelated individuals with predominantly estimated European genetic ancestry in UK Biobank.
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Jun 3, 2024 | 
nature.com | Rahul Gupta |Masahiro Kanai |Timothy Durham |Anna V. Kotrys |Wei Zhou |Konrad J Karczewski | +1 more
Correction to: Nature https://doi.org/10.1038/s41586-023-06426-5Published online 16 August 2023When performing a genome-wide association study (GWAS), the choice of which allele (reference vs. alternate) is considered the “effect allele” is arbitrary. In our computations, we chose the reference allele. For a small subset of our results, the effect sizes were erroneously attributed to the alternate allele.
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Jan 15, 2024 | 
nature.com | Masahiro Kanai |Qingbo Wang |Jessica Alföldi |William Phu |Yossi Farjoun |Anne H. O’Donnell-Luria | +4 more
Correction to: Nature https://doi.org/10.1038/s41586-023-06045-0 Published online 6 December 2023In the version of this article initially published, data points did not appear in Supplementary Figs. 6–8, and are now included in the online version of the Supplementary Information. About this articleChen, S., Francioli, L.C., Goodrich, J.K. et al. Author Correction: A genomic mutational constraint map using variation in 76,156 human genomes. Nature (2024).
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Dec 6, 2023 | 
nature.com | Masahiro Kanai |Qingbo Wang |Jessica Alföldi |Yossi Farjoun |Anne H. O’Donnell-Luria |Alicia Martin | +4 more
AbstractThe depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1,2,3,4, but attempts to assess constraint for non-protein-coding regions have proved more difficult.
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Dec 6, 2023 | 
nature.com | Laurent C. Francioli |Sarah Stenton |Samantha Baxter |Benjamin M. Neale |Joel N. Hirschhorn |Heidi Rehm | +3 more
AbstractRecessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings.
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Nov 30, 2023 | 
nature.com | Ran Ji Cui |Roy A Elzur |Masahiro Kanai |Jacob C. Ulirsch |Mark Daly |Benjamin M. Neale
AbstractFine-mapping aims to identify causal genetic variants for phenotypes. Bayesian fine-mapping algorithms (for example, SuSiE, FINEMAP, ABF and COJO-ABF) are widely used, but assessing posterior probability calibration remains challenging in real data, where model misspecification probably exists, and true causal variants are unknown. We introduce replication failure rate (RFR), a metric to assess fine-mapping consistency by downsampling.
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Aug 16, 2023 | 
nature.com | Rahul Gupta |Masahiro Kanai |Timothy Durham |Anna V. Kotrys |Wei Zhou |Konrad J Karczewski | +1 more
AbstractMitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation1. Heteroplasmy refers to the presence of a mixture of mtDNA alleles in an individual and has been associated with disease and ageing. Mechanisms underlying common variation in human heteroplasmy, and the influence of the nuclear genome on this variation, remain insufficiently explored.
