Author Correction: The mutational constraint spectrum quantified from variation in 141,456 humans

Karczewski, Konrad J.; Francioli, Laurent C.; Tiao, Grace; Cummings, Beryl B.; Alföldi, Jessica; Wang, Qingbo; Collins, Ryan L.; Laricchia, Kristen M.; Ganna, Andrea; Birnbaum, Daniel; Gauthier, Laura D.; Brand, Harrison; Solomonson, Matthew; Watts, Nicholas A.; Rhodes, Daniel R.; Singer-Berk, Moriel; England, Eleina; Seaby, Eleanor G.; Kosmicki, Jack A.; Walters, Raymond; Tashman, Katherine; Farjoun, Yossi; Banks, Eric; Poterba, Timothy; Wang, Arcturus; Seed, Cotton; Whiffin, Nicola; Chong, Jessica X.; Samocha, Kaitlin E.; Pierce‐Hoffman, Emma; Zappala, Zachary; O’Donnell-Luria, Anne H.; Minikel, Eric Vallabh; Weisburd, Ben; Lek, Monkol; Ware, James S; Vittal, Christopher; Armean, Irina M.; Bergelson, Louis; Cibulskis, Kristian; Connolly, Kristen M.; Covarrubias, Miguel; Donnelly, Stacey; Ferriera, Steven; Gabriel, Stacey; Gentry, Jeff; Gupta, Namrata; Jeandet, Thibault; Kaplan, Diane; Llanwarne, Christopher; Munshi, Ruchi; Novod, Sam; Petrillo, Nikelle; Roazen, David; Ruano-Rubio, Valentín; Saltzman, Andrea; Schleicher, Molly; Soto, José María Satizábal; Tibbetts, Kathleen; Tolonen, Charlotte; Wade, Gordon; Talkowski, Michael E.; Neale, Benjamin M.; Daly, Mark J.; MacArthur, Daniel G.

doi:10.1038/s41586-020-03174-8

Cited by 904 publications

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“…For population frequency data we use gnomAD v3 SNP frequency data for N ∼ 32, 000 non-Finnish Europeans Karczewski et al (2021 ). The average heterozygosity of non disease-associated SNPs over this cohort is ⟨Θ⟩ nSNP = 0.14, while that of disease-associated SNPs is nearly 50 times lower, ⟨Θ⟩ dSNP = 0 0029.. Figure 3 shows the mean heterozygosity of nSNPs and dSNPs binned by the maximal blob hydrophobicity ( H max ) for each SNP (see Methods).…”

Section: Resultsmentioning

confidence: 99%

Contiguously-hydrophobic sequences are functionally significant throughout the human exome

Lohia

Hansen

Brannigan

2021

Preprint

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Hydrophobic interactions have long been established as essential to stabilizing structured proteins as well as drivers of aggregation, but the impact of hydrophobicity on the functional significance of sequence variants has rarely been considered in a genome-wide context. Here we test the role of hydrophobicity on functional impact using a set of 70,000 disease and non-disease associated single nucleotide polymorphisms (SNPs), using enrichment of disease-association as an indicator of functionality. We find that functional impact is uncorrelated with hydrophobicity of the SNP itself, and only weakly correlated with the average local hydrophobicity, but is strongly correlated with both the size and minimum hydrophobicity of the contiguous hydrophobic domain that contains the SNP. Disease-association is found to vary by more than 6-fold as a function of contiguous hydrophobicity parameters, suggesting utility as a prior for identifying causal variation. We further find signatures of differential selective constraint on domain hydrophobicity, and that SNPs splitting a long hydrophobic region or joining two short regions of contiguous hydrophobicity are particularly likely to be disease-associated. Trends are preserved for both aggregating and non-aggregating proteins, indicating that the role of contiguous hydrophobicity extends well beyond aggregation risk.

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Section: Resultsmentioning

confidence: 99%

Contiguously-hydrophobic sequences are functionally significant throughout the human exome

Lohia

Hansen

Brannigan

2021

Preprint

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“…The following web resources were used to document different relevant information as follows: Data from Deciphering the Mechanisms of Developmental Disorders (https:/ dmdd.org.uk ), a program funded by the Wellcome Trust with support from the Francis Crick Institute, is licensed under a Creative Commons Attribution license and was used for the phenotype of Ehbp111 knockout mice. Genome Aggregation Database https://gnomad.broadinstitute.org [ 11 ] was used to check the frequency of identified variants in different populations. Pfam database, http://pfam.xfam.org/ [ 12 ], was used to determine protein domains and map the mutated base.…”

Section: Methodsmentioning

confidence: 99%

Lethal variants in humans: lessons learned from a large molecular autopsy cohort

et al. 2021

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Background Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans. Methods We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels. Results The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results. Conclusions Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.

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“…These are damaging variants: "transcript_ablation", "splice_acceptor_variant", "splice_donor_variant", "stop_gained", "frameshift_variant", "stop_loss", "start_loss", or missense variants with MPC 82 (Missense Badness, PolyPhen-2, and Constraint) scores >2 . We further restricted data to variants in constrained genes with a LOEUF score < 0.37 83 , which represents the topmost decile of constrained genes. For SVs, we restricted data to SVs affecting the most constrained genes i.e., LOEUF score < 0.37, representing the first decile of most constrained genes.…”

Section: Polygenic Scoresmentioning

confidence: 99%

Genetic correlates of phenotypic heterogeneity in autism

Warrier

Leblond

Cliquet

et al. 2020

Preprint

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Importance Schizophrenia, educational attainment, and intelligence are all genetically correlated with autism. However, autism is a complex condition, with several different core (such as social communication difficulties and repetitive and restricted behaviour) and associated features (such as IQ and adaptive behaviour) contributing to the underlying heterogeneity. It is unknown to what extent polygenic scores (PGS) for these three phenotypes are associated with the core and associated autism features. Objective To investigate the association of PGS for intelligence, educational attainment and schizophrenia on core autism features, IQ and adaptive behaviour in autistic individuals. To further investigate the effects of stratifying by sex and IQ on these associations. Design PGS association for the three phenotypes with 12 different autism core and associated features in three cohorts followed by meta-analysis. We additionally conducted sensitivity analyses by stratifying for sex and IQ. Settings Three cross-sectional, multi-centre cohorts comprising autistic with genotype data, and phenotypic information. Participants Autistic individuals (total N: 2,512 to 3,681) from three different cohorts: Simons Simplex Collection (Nmax = 2,233), Autism Genetic Research Exchange (Nmax = 1,200), and AIMS-2-TRIALS LEAP (Nmax = 262) Main outcome measures Association of PGS for intelligence, educational attainment, and schizophrenia with core autism features, measures of intelligence, and adaptive behaviour in autistic individuals Results We identified a similar pattern of correlation among core and associated autism features across all three cohorts. Cluster analyses of these features identified two broad clusters: one consisting of the core features, and another consisting of IQ and adaptive behaviour. PGS for intelligence were only associated with measures of intelligence and adaptive behaviour (e.g. for full-scale IQ, Beta = 0.08, 95%CI = 0.11 to 0.04) for PGS for educational attainment were associated for measures of intelligence, adaptive behaviour, and additionally, non-verbal communication as measured by ADI which is a core-autism feature (e.g. for full-scale IQ, Beta = 0.05, 95% CI = 0.08 to 0.02; for ADI non-verbal communication, Beta = 0.05, 95% CI = 0.09 tp 0.01). Finally, PGS for schizophrenia were associated with two core autism features: restricted and repetitive behaviour and verbal communication difficulties as measured by the ADI-R (e.g. for ADI restricted and repetitive behaviour: Beta = 0.06, 95% CI = 0.09 to 0.02). Most of these associations were also significant when restricting it to males only or to individuals with IQ > 70. We find limited evidence for heterogeneity between cohorts. Conclusion and relevance We identify specific and different patterns of association between PGS for the three phenotypes and core and associated autism features. This provides greater resolution into the shared genetics between autism and the three phenotypes, and suggests one method to investigate heterogeneity in autism and co-occurring conditions.

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Author Correction: The mutational constraint spectrum quantified from variation in 141,456 humans

Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03174-8.

Cited by 904 publications

References 0 publications

Contiguously-hydrophobic sequences are functionally significant throughout the human exome

Contiguously-hydrophobic sequences are functionally significant throughout the human exome

Lethal variants in humans: lessons learned from a large molecular autopsy cohort

Genetic correlates of phenotypic heterogeneity in autism

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