A flexible modeling and inference framework for estimating variant effect sizes from GWAS summary statistics DOI Creative Commons
Jeffrey P. Spence, Nasa Sinnott-Armstrong, Themistocles L. Assimes

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Апрель 19, 2022

Abstract Genome-wide association studies (GWAS) have highlighted that almost any trait is affected by many variants of relatively small effect. On one hand this presents a challenge for inferring the effect single variant as signal-to-noise ratio high This compounded when combining information across in polygenic scores predicting values. other hand, large number contributing provides an opportunity to learn about average behavior encoded distribution sizes. Many approaches looked at aspects problem, but no method has unified inference effects individual with sizes while requiring only GWAS summary statistics and properly accounting linkage disequilibrium between variants. Here we present flexible, unifying framework combines infer uses improve estimation We also develop variational (VI) scheme perform efficient under framework. show useful constructing (PGSs) outperform state-of-the-art. Our modeling easily extends jointly multiple cohorts, where building PGSs using additional cohorts differing ancestries improves predictive accuracy portability. investigate inferred distributions traits find these ranging over orders magnitude, contrast assumptions implicit commonly-used statistical genetics methods.

Язык: Английский

Population differentiation of polygenic score predictions under stabilizing selection DOI Creative Commons
Sivan Yair, Graham Coop

Philosophical Transactions of the Royal Society B Biological Sciences, Год журнала: 2022, Номер 377(1852)

Опубликована: Апрель 18, 2022

Given the many small-effect loci uncovered by genome-wide association studies (GWAS), polygenic scores have become central to genomic medicine, and found application in diverse settings including evolutionary of adaptation. Despite their promise, been suffer from limited portability across human populations. This at first seems conflict with observation that most common genetic variation is shared among We investigate one potential cause this discrepancy: stabilizing selection on complex traits. Counterintuitively, while constrains phenotypic evolution, it accelerates loss fixation alleles underlying trait within populations (GWAS loci). Thus even when share an optimum phenotype, erodes variance contributed GWAS loci, such predictions population explain less another. develop theory quantify how expected reduce prediction accuracy not represented samples. In addition, we find can substantially overstate average differences phenotypes emphasize around a as useful null model connect patterns allele frequency score differentiation. article part theme issue 'Celebrating 50 years since Lewontin's apportionment diversity'.

Язык: Английский

Процитировано

47
Quantifying portable genetic effects and improving cross-ancestry genetic prediction with GWAS summary statistics DOI Creative Commons
Jiacheng Miao, Hanmin Guo,

Gefei Song

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Фев. 14, 2023

Abstract Polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of Europeans are known to have substantially reduced predictive accuracy in non-European populations, limiting their clinical utility and raising concerns about health disparities across ancestral populations. Here, we introduce a statistical framework named X-Wing improve performance ancestrally diverse quantifies local genetic correlations for complex traits between employs an annotation-dependent estimation procedure amplify correlated effects combines multiple population-specific PRS into unified score with GWAS summary statistics alone as input. Through extensive benchmarking, demonstrate that pinpoints portable improves showing 14.1%–119.1% relative gain R 2 compared state-of-the-art methods based on statistics. Overall, addresses critical limitations existing approaches may broad applications cross-population polygenic prediction.

Язык: Английский

Процитировано

32
Evolutionary Genetics and Admixture in African Populations DOI Creative Commons
Aaron Pfennig, Lindsay N. Petersen,

Paidamoyo Kachambwa

и другие.

Genome Biology and Evolution, Год журнала: 2023, Номер 15(4)

Опубликована: Март 29, 2023

Abstract As the ancestral homeland of our species, Africa contains elevated levels genetic diversity and substantial population structure. Importantly, African genomes are heterogeneous: They contain mixtures multiple ancestries, each which have experienced different evolutionary histories. In this review, we view genetics through lens admixture, highlighting how demographic events shaped genomes. Each these historical vignettes paints a recurring picture divergence followed by secondary contact. First, give brief overview variation in examine deep structure within Africa, including evidence ancient introgression from archaic “ghost” populations. Second, describe legacies admixture that occurred during past 10,000 years. This includes gene flow between click-speaking Khoe-San populations, stepwise spread pastoralism eastern to southern migrations Bantu speakers across continent, as well Middle East Europe into Sahel region North Africa. Furthermore, genomic signatures more recent can be found Cape Peninsula throughout diaspora. Third, highlight natural selection has patterns noting provides potent source adaptive selective pressures vary Finally, explore biomedical implications on health disease call for ethically conducted studies

Язык: Английский

Процитировано

32
Inferring disease architecture and predictive ability with LDpred2-auto DOI
Florian Privé, Clara Albiñana, Julyan Arbel

и другие.

The American Journal of Human Genetics, Год журнала: 2023, Номер 110(12), С. 2042 - 2055

Опубликована: Ноя. 8, 2023

Язык: Английский

Процитировано

26
Polygenic scores in cancer DOI
Xin Yang, Siddhartha Kar, Antonis C. Antoniou

и другие.

Nature reviews. Cancer, Год журнала: 2023, Номер 23(9), С. 619 - 630

Опубликована: Июль 21, 2023

Язык: Английский

Процитировано

25
Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes DOI Creative Commons
Hüsün Sheyma Kizilkaya, Kimmie V. Sørensen, Jakob Sture Madsen

и другие.

Nature Metabolism, Год журнала: 2024, Номер 6(7), С. 1268 - 1281

Опубликована: Июнь 13, 2024

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes

Язык: Английский

Процитировано

15
Multi-Ancestry Polygenic Risk Score for Coronary Heart Disease Based on an Ancestrally Diverse Genome-Wide Association Study and Population-Specific Optimization DOI
Johanna L. Smith, Catherine Tcheandjieu, Ozan Dikilitas

и другие.

Circulation Genomic and Precision Medicine, Год журнала: 2024, Номер 17(3)

Опубликована: Фев. 21, 2024

Predictive performance of polygenic risk scores (PRS) varies across populations. To facilitate equitable clinical use, we developed PRS for coronary heart disease (CHD;

Язык: Английский

Процитировано

11
Large-scale cross-ancestry genome-wide meta-analysis of serum urate DOI Creative Commons
Chamlee Cho, Beomsu Kim,

Dan Say Kim

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Апрель 24, 2024

Abstract Hyperuricemia is an essential causal risk factor for gout and associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies serum urate, genetic architecture urate requires exploration. A large-scale cross-ancestry meta-analysis 1,029,323 individuals ancestry-specific identifies a total 351 loci, including 17 previously unreported loci. The control similar between European populations. transcriptome-wide study, enrichment analysis, colocalization analysis in relevant tissues identify candidate urate-associated genes, CTBP1 , SKIV2L WWP2 . phenome-wide study using polygenic scores urate-correlated diseases heart failure hypertension. Mendelian randomization mediation analyses show that genes might have relationship via effects. This elucidates our understanding control.

Язык: Английский

Процитировано

11
Screening embryos for polygenic disease risk: a review of epidemiological, clinical, and ethical considerations DOI Creative Commons
Antonio Capalbo,

G. de Wert,

Heidi Mertes

и другие.

Human Reproduction Update, Год журнала: 2024, Номер 30(5), С. 529 - 557

Опубликована: Май 28, 2024

The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural and aneuploidy. Recent advances have made genome-wide genotyping IVF feasible affordable, raising the possibility screening for their risk polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called embryo (PES; also PGT-P), it is already available patients some countries. Several articles studied epidemiological, clinical, ethical perspectives on PES; however, comprehensive, principled review emerging field missing.

Язык: Английский

Процитировано

11
Multi-omics approaches for understanding gene-environment interactions in noncommunicable diseases: techniques, translation, and equity issues DOI Creative Commons

Robel Alemu,

Nigussie Tadesse Sharew,

Yodit Y. Arsano

и другие.

Human Genomics, Год журнала: 2025, Номер 19(1)

Опубликована: Янв. 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.

Язык: Английский

Процитировано

1