Genetic and molecular architecture of complex traits

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1059 - 1075

Published: Feb. 1, 2024

Language: Английский

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Multi-omics approaches for understanding gene-environment interactions in noncommunicable diseases: techniques, translation, and equity issues

Human Genomics, Journal Year: 2025, Volume and Issue: 19(1)

Published: Jan. 31, 2025

Non-communicable diseases (NCDs) such as cardiovascular diseases, chronic respiratory cancers, diabetes, and mental health disorders pose a significant global challenge, accounting for the majority of fatalities disability-adjusted life years worldwide. These arise from complex interactions between genetic, behavioral, environmental factors, necessitating thorough understanding these dynamics to identify effective diagnostic strategies interventions. Although recent advances in multi-omics technologies have greatly enhanced our ability explore interactions, several challenges remain. include inherent complexity heterogeneity multi-omic datasets, limitations analytical approaches, severe underrepresentation non-European genetic ancestries most omics which restricts generalizability findings exacerbates disparities. This scoping review evaluates landscape data related NCDs 2000 2024, focusing on advancements integration, translational applications, equity considerations. We highlight need standardized protocols, harmonized data-sharing policies, advanced approaches artificial intelligence/machine learning integrate study gene-environment interactions. also opportunities translating insights (GxE) research into precision medicine strategies. underscore potential advancing enhancing patient outcomes across diverse underserved populations, emphasizing fairness-centered strategic investments build local capacities underrepresented populations regions.

Language: Английский

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A Litmus Test for Confounding in Polygenic Scores

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

Abstract Polygenic scores (PGSs) are being rapidly adopted for trait prediction in the clinic and beyond. PGSs often thought of as capturing direct genetic effect one’s genotype on their phenotype. However, because constructed from population-level associations, they influenced by factors other than effects, including stratification, assortative mating, dynastic effects (“SAD effects”). Our interpretation application may hinge relative impact SAD since be environmentally or culturally mediated. We developed a method that estimates proportion variance PGS (in given sample) is driven covariance. leverage comparison interest based standard GWAS with sibling GWAS—which largely immune to effects—to quantify contribution each type interest. method, Partitioning Genetic Scores Using Siblings (PGSUS, pron. “Pegasus”), breaks down components further axes ancestry, allowing nuanced effects. In particular, PGSUS can detect stratification along major ancestry well “isotropic” respect ancestry. Applying PGSUS, we found evidence using large meta-analyses height educational attainment range UK Biobank. some instances, appears stratified axis one sample but not another (for example, comparisons samples different countries, ancient DNA vs. contemporary samples). Finally, show approaches adjustment population structure GWASs have distinct advantages mitigation ancestry-axis-specific isotropic PGS. study illustrates how family-based designs combined population-based guide genomic predictors.

Language: Английский

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Genetic basis of partner choice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Abstract Previous genetic studies of human assortative mating have primarily focused on searching for its genomic footprint but revealed limited insights into biological and social mechanisms. Combining from the economics marriage market with advanced tools in statistical genetics, we perform first genome-wide association study (GWAS) a latent index partner choice. Using 206,617 individuals four global cohorts, uncover phenotypic characteristics processes underlying mating. We identify broadly robust component choice between sexes several countries correlates. also provide solutions to reduce mating-driven biases complex traits by conditioning GWAS summary statistics associations index.

Language: Английский

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Examining intergenerational risk factors for conduct problems using polygenic scores in the Norwegian Mother, Father and Child Cohort Study

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(4), P. 951 - 961

Published: Jan. 16, 2024

The aetiology of conduct problems involves a combination genetic and environmental factors, many which are inherently linked to parental characteristics given parents' central role in children's lives across development. It is important disentangle what extent links between heritable behaviour due transmission risk or indirect influences via the environment (i.e., nurture). We used 31,290 genotyped mother-father-child trios from Norwegian Mother, Father Child Cohort Study (MoBa), testing nurture effects on using 13 polygenic scores (PGS) spanning psychiatric conditions, substance use, education-related other factors. Maternal self-reports at ages 8 14 years were available for up 15,477 children. found significant 12 out PGS age (strongest association: smoking, β = 0.07, 95% confidence interval [0.05, 0.08]) 4 externalising problems, 0.08, 0.11]). Conversely, we did not find our selection PGS. Our findings provide evidence association child problems. results may also indicate that traits indexed by limited aetiological importance problems-though small magnitude captured included remain possibility.

Language: Английский

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Genetic associations between non-cognitive skills and academic achievement over development

Nature Human Behaviour, Journal Year: 2024, Volume and Issue: 8(10), P. 2034 - 2046

Published: Aug. 26, 2024

Abstract Non-cognitive skills, such as motivation and self-regulation, are partly heritable predict academic achievement beyond cognitive skills. However, how the relationship between non-cognitive skills changes over development is unclear. The current study examined associated with from ages 7 to 16 years in a sample of 10,000 children England Wales. results showed that association increased across development. Twin polygenic scores analyses found links genetics became stronger school years. within-family indicated genetic effects on could not simply be attributed confounding by environmental differences nuclear families, consistent possible role for evocative/active gene–environment correlations. By studying associations through developmental lens, we provide further insights into

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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Estimation of indirect genetic effects and heritability under assortative mating

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

Published: July 11, 2023

Abstract Both direct genetic effects (effects of alleles in an individual on that individual) and indirect — (e.g. parents) another offspring) can contribute to phenotypic variation genotype-phenotype associations. Here, we consider a phenotype affected by parental under assortative mating at equilibrium. We generalize classical theory derive decomposition the equilibrium variance terms effect components. extend this show popular methods for estimating or ‘genetic nurture’ through analysis offspring polygenic predictors (called indices scores PGIs PGSs) are substantially biased mating. propose improved method while accounting also correct heritability estimates bias due validate our simulations apply it height educational attainment (EA), is 0.699 (S.E. = 0.075) finding no evidence height. estimate very high correlation between parents’ underlying components EA, 0.755 0.035), which inconsistent with twin based possibly confounding EA PGI and/or studies. implement software package snipar , enabling researchers data including observed imputed genotypes. provide theoretical framework understanding results analyses practical methodology

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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Causal interpretations of family GWAS in the presence of heterogeneous effects

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(38)

Published: Sept. 13, 2024

Family-based genome-wide association studies (GWASs) are often claimed to provide an unbiased estimate of the average causal effects (or treatment effects; ATEs) alleles, on basis analogy between random transmission alleles from parents children and a randomized controlled trial. We show that this claim does not hold in general. Because Mendelian segregation only randomizes among heterozygotes, homozygotes observable. This feature will matter if allele has different as can arise presence gene-by-environment interactions, gene-by-gene or differences linkage disequilibrium patterns. At single locus, family-based GWAS be thought providing effect heterozygotes (i.e., local effect; LATE). interpretation extend polygenic scores (PGSs), however, because sets SNPs heterozygous each family. Therefore, other than under specific conditions, within-family regression slope PGS cannot assumed LATE for any subset weighted families. In practice, potential biases likely smaller those confounding standard, population-based GWAS, so family remain important dissection genetic contributions phenotypic variation. Nonetheless, their is less straightforward been widely appreciated.

Language: Английский

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