Mexican Biobank advances population and medical genomics of diverse ancestries

Nature, Journal Year: 2023, Volume and Issue: 622(7984), P. 775 - 783

Published: Oct. 11, 2023

Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories complex trait architectures remain hidden owing insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural urban localities across all 32 states Mexico at a resolution of 1.8 million genome-wide markers with linked disease information creating valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution inference identity-by-descent segments, we inferred ancestral population sizes Mesoamerican regions over time, unravelling Indigenous, colonial postcolonial demographic dynamics2-6. We observed variation runs homozygosity among genomic different ancestries reflecting distinct and, turn, distributions rare deleterious variants. conducted association studies (GWAS) for 22 traits found that several are better predicted GWAS compared UK GWAS7,8. identified environmental factors associating variation, such as length genome predictor body mass index, triglycerides, glucose height. This study provides insights into dissects their architectures, both crucial making precision preventive medicine initiatives accessible worldwide.

Language: Английский

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Interpreting population- and family-based genome-wide association studies in the presence of confounding

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(4), P. e3002511 - e3002511

Published: April 11, 2024

A central aim of genome-wide association studies (GWASs) is to estimate direct genetic effects: the causal effects on an individual’s phenotype alleles that they carry. However, estimates can be subject and environmental confounding also absorb “indirect” relatives’ genotypes. Recently, important development in controlling for these confounds has been use within-family GWASs, which, because randomness mendelian segregation within pedigrees, are often interpreted as producing unbiased effects. Here, we present a general theoretical analysis influence standard population-based GWASs. We show that, contrary common interpretation, family-based biased by confounding. In humans, such biases will small per-locus, but compounded when effect-size used polygenic scores (PGSs). illustrate population- using models assortative mating, population stratification, stabilizing selection GWAS traits. further how indirect effects, based comparisons parentally transmitted untransmitted alleles, suffer substantial conclude while have placed estimation more rigorous footing, carry subtle issues interpretation arise from

Language: Английский

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Bayesian estimation of gene constraint from an evolutionary model with gene features

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(8), P. 1632 - 1643

Published: July 8, 2024

Language: Английский

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Genetic association data are broadly consistent with stabilizing selection shaping human common diseases and traits

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 23, 2024

Abstract Results from genome-wide association studies (GWAS) enable inferences about the balance of evolutionary forces maintaining genetic variation underlying common diseases and other genetically complex traits. Natural selection is a major force shaping variation, understanding it necessary to explain architecture prevalence heritable diseases. Here, we analyze data for 27 traits, including anthropometric metabolic binary diseases—both early-onset post-reproductive. We develop an inference framework test existing population genetics models based on joint distribution allelic effect sizes frequencies trait-associated variants. A majority traits have GWAS results that are inconsistent with neutral evolution or long-term directional (selection against trait disease risk). Instead, find most show consistency stabilizing selection, which acts preserve intermediate value risk. Our observations also suggest may reflect pleiotropy, each variant influenced by associations multiple selected

Language: Английский

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Interpreting population and family-based genome-wide association studies in the presence of confounding

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 27, 2023

Abstract A central aim of genome-wide association studies (GWASs) is to estimate direct genetic effects: the causal effects on an individual’s phenotype alleles that they carry. However, estimates can be subject and environmental confounding, also absorb ‘indirect’ relatives’ genotypes. Recently, important development in controlling for these confounds has been use within-family GWASs, which, because randomness Mendelian segregation within pedigrees, are often interpreted as producing unbiased effects. Here, we present a general theoretical analysis influence confounding standard population-based GWASs. We show that, contrary common interpretation, family-based biased by confounding. In humans, such biases will small per-locus, but compounded when effect size used polygenic scores. illustrate population- using models assortative mating, population stratification, stabilizing selection GWAS traits. further how indirect effects, based comparisons parentally transmitted untransmitted alleles, suffer substantial addition known arise GWASs interactions between family members ignored, from gene-by-environment (G×E) parental genotypes not distributed identically across interacting backgrounds. conclude while have placed estimation more rigorous footing, carry subtle issues interpretation interactions.

Language: Английский

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Tree-based QTL mapping with expected local genetic relatedness matrices

The American Journal of Human Genetics, Journal Year: 2023, Volume and Issue: 110(12), P. 2077 - 2091

Published: Dec. 1, 2023

Language: Английский

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Conditional frequency spectra as a tool for studying selection on complex traits in biobanks

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 17, 2024

Abstract Natural selection on complex traits is difficult to study in part due the ascertainment inherent genome-wide association studies (GWAS). The power detect a trait-associated variant GWAS function of frequency and effect size — but for under selection, determines strength against it, constraining its frequency. To account ascertainment, we propose studying joint distribution allele frequencies across populations, conditional cohort. Before considering these spectra, first characterized impact non-equilibrium demography dynamics forwards backwards time. We then used results understand spectra realistic human demography. Finally, investigated empirical variants associated with 106 traits, finding compelling evidence either stabilizing or purifying selection. Our provide insight into polygenic score portability other properties ascertained GWAS, highlighting utility spectra.

Language: Английский

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The effect of long-range linkage disequilibrium on allele-frequency dynamics under stabilizing selection

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 28, 2024

Abstract Stabilizing selection on a polygenic trait reduces the trait’s genetic variance by (i) generating correlations (linkage disequilibria) between opposite-effect alleles throughout genome and (ii) selecting against rare at polymorphic loci that affect trait, eroding heterozygosity these loci. Here, we characterize impact of linkage disequilibria, which stabilizing generates rapid timescale, subsequent allele-frequency dynamics individual loci, proceed slower timescale. We obtain expressions for expected per-generation change in minor-allele frequency as functions effect sizes strength its heritability, relations among Using whole-genome simulations, show our predict under more accurately than have previously been used this purpose. Our results implications understanding architecture complex traits.

Language: Английский

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Predicting the direction of phenotypic difference

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 23, 2024

Predicting phenotypes from genomic data is a key goal in genetics, but for most complex phenotypes, predictions are hampered by incomplete genotype-to-phenotype mapping. Here, we describe more attainable approach than quantitative predictions, which aimed at qualitatively predicting phenotypic differences. Despite mapping, show that it relatively easy to determine of two individuals has greater value. This question central many scenarios, e.g., comparing disease risk between individuals, the yield crop strains, or anatomy extinct vs extant species. To evaluate prediction accuracy, i.e., probability individual with predicted phenotype indeed value, developed an estimator ratio known and unknown effects on phenotype. We evaluated accuracy using human tens thousands either same family population, as well different found that, cases, even when only small fraction loci affecting known, value can be identified over 90% accuracy. Our also circumvents some limitations transferring genetic association results across populations. Overall, introduce enables accurate information - direction difference suggest extracted previously appreciated.

Language: Английский

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Unifying approaches from statistical genetics and phylogenetics for mapping phenotypes in structured populations

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(10), P. e3002847 - e3002847

Published: Oct. 9, 2024

In both statistical genetics and phylogenetics, a major goal is to identify correlations between genetic loci or other aspects of the phenotype environment focal trait. these 2 fields, there are sophisticated but disparate traditions aimed at tasks. The disconnect their respective approaches becoming untenable as questions in medicine, conservation biology, evolutionary biology increasingly rely on integrating data from within among species, once-clear conceptual divisions blurred. To help bridge this divide, we lay out general model describing covariance contributions quantitative phenotypes different individuals. Taking approach shows that standard models (e.g., genome-wide association studies; GWAS) phylogenetic comparative regression) can be interpreted special cases more quantitative-genetic model. fact share same core architecture means build unified understanding strengths limitations methods for controlling structure when testing associations. We develop intuition why spurious may occur analytically conduct population-genetic simulations traits. structural similarity problems phylogenetics enables us take methodological advances one field apply them other. demonstrate by showing how GWAS technique-including relatedness matrix (GRM) well its leading eigenvectors, corresponding principal components genotype matrix, regression model-can mitigate analyses. As case study, re-examine an analysis coevolution expression levels genes across fungal phylogeny show including eigenvectors covariates decreases false positive rate while simultaneously increasing true rate. More generally, work provides foundation integrative processes shape it.

Language: Английский

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