Calibrated prediction intervals for polygenic scores across diverse contexts DOI Creative Commons
Kangcheng Hou,

Ziqi Xu,

Yi Ding

et al.

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

Published: July 27, 2023

Polygenic scores (PGS) have emerged as the tool of choice for genomic prediction in a wide range fields from agriculture to personalized medicine. We analyze data two large biobanks US (All Us) and UK (UK Biobank) find widespread variability PGS performance across contexts. Many contexts, including age, sex, income, impact accuracies with similar magnitudes genetic ancestry. PGSs trained single versus multi-ancestry cohorts show context-specificity their accuracies. introduce trait intervals that are allowed vary contexts principled approach account context-specific accuracy prediction. model all joint framework enable PGS-based predictions well-calibrated (contain value 90% probability contexts), whereas methods ignore context mis-calibrated. need be adjusted considered traits ranging 10% diastolic blood pressure 80% waist circumference. Adjustment depends on dataset; example, education years by All Us 8% Biobank. Our results provide path forward towards utilization individuals regardless while highlighting importance comprehensive profile information study design collection.

Language: Английский

The genetic architecture and evolution of the human skeletal form DOI Open Access
Eucharist Kun, Emily Javan, Olivia S. Smith

et al.

Science, Journal Year: 2023, Volume and Issue: 381(6655)

Published: July 20, 2023

The human skeletal form underlies bipedalism, but the genetic basis of proportions (SPs) is not well characterized. We applied deep-learning models to 31,221 x-rays from UK Biobank extract a comprehensive set SPs, which were associated with 145 independent loci genome-wide. Structural equation modeling suggested that limb exhibited strong sharing width and torso proportions. Polygenic score analysis identified specific associations between osteoarthritis hip knee SPs. In contrast other traits, SP enriched in accelerated regions regulatory elements genes are differentially expressed humans great apes. Combined, our work identifies variants affect ties major evolutionary facet anatomical change pathogenesis.

Language: Английский

Citations

54
Calibrated prediction intervals for polygenic scores across diverse contexts DOI
Kangcheng Hou,

Ziqi Xu,

Yi Ding

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(7), P. 1386 - 1396

Published: June 17, 2024

Language: Английский

Citations

21
Contribution of autosomal rare and de novo variants to sex differences in autism DOI Creative Commons
Mahmoud Koko, F. Kyle Satterstrom, Varun Warrier

et al.

The American Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Autism is four times more prevalent in males than females. To study whether this reflects a difference genetic predisposition attributed to autosomal rare variants, we evaluated sex differences effect size of damaging protein-truncating and missense variants on autism 47,061 autistic individuals using liability model with differing thresholds. Given the rates cognitive impairment among individuals, also compared sizes between without or motor delay. Although these mediated different likelihoods versus difficulties, their scale did not differ significantly by exome wide genes sex-differentially expressed cortex. De novo mutations were enriched male-biased expression adult cortex, but show significant scale, nor conferred from other similar loss-of-function intolerance sex-averaged cortical expression. Exome-wide female bias de mutation observed was driven high-confidence syndromic autism-predisposition genes. In summary, coding confer for females males.

Language: Английский

Citations

3
Genome-wide association study of obstructive sleep apnoea in the Million Veteran Program uncovers genetic heterogeneity by sex DOI Creative Commons
Tamar Sofer,

Nuzulul Kurniansyah,

Michael Murray

et al.

EBioMedicine, Journal Year: 2023, Volume and Issue: 90, P. 104536 - 104536

Published: March 28, 2023

Genome-wide association studies (GWAS) for obstructive sleep apnoea (OSA) are limited due to the underdiagnosis of OSA, leading misclassification which consequently reduces statistical power. We performed a GWAS OSA in Million Veteran Program (MVP) U.S. Department Veterans Affairs (VA) healthcare system, where prevalence is close its true population prevalence.

Language: Английский

Citations

29
Quality control and analytic best practices for testing genetic models of sex differences in large populations DOI Creative Commons
Ekaterina Khramtsova, Melissa A. Wilson, Joanna Martin

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(10), P. 2044 - 2061

Published: May 1, 2023

Language: Английский

Citations

27
Unveiling recent and ongoing adaptive selection in human populations DOI Creative Commons
Ziyue Gao

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(1), P. e3002469 - e3002469

Published: Jan. 18, 2024

Genome-wide scans for signals of selection have become a routine part the analysis population genomic variation datasets and resulted in compelling evidence during recent human evolution. This Essay spotlights methodological innovations that enabled detection over very timescales, even contemporary populations. By harnessing large-scale phenotypic datasets, these new methods use different strategies to uncover connections between genotype, phenotype, fitness. outlines rationale key findings each strategy, discusses challenges interpretation, describes opportunities improve understanding ongoing

Language: Английский

Citations

15
Genotype × environment interactions in gene regulation and complex traits DOI
Carly Boye, Shreya Nirmalan, Ali Ranjbaran

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Language: Английский

Citations

13
Sex-specific genetic architecture of blood pressure DOI
Min‐Lee Yang, Chang Xu, Trisha Gupte

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(3), P. 818 - 828

Published: March 1, 2024

Language: Английский

Citations

12
Relationship between sex biases in gene expression and sex biases in autism and Alzheimer’s disease DOI Creative Commons

Stuart B. Fass,

Bernard Mulvey, Rebecca Chase

et al.

Biology of Sex Differences, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 7, 2024

Abstract Background Sex differences in the brain may play an important role sex-differential prevalence of neuropsychiatric conditions. Methods In order to understand transcriptional basis sex differences, we analyzed multiple, large-scale, human postmortem RNA-Seq datasets using both within-region and pan-regional frameworks. Results We find evidence sex-biased transcription many autosomal genes, some which provide for pathways cell population between chromosomally male female individuals. These analyses also highlight regional extent gene expression. observe increase specific neuronal transcripts brains immune glial function-related brains. Integration with single-nucleus data suggests this corresponds cellular states rather than abundance. case–control expression studies a molecular predisposition towards Alzheimer’s disease, female-biased disease. Autism, male-biased diagnosis, does not exhibit pattern our analysis. Conclusion Overall, these mechanisms by interact conditions brain. Furthermore, region-specific enable additional at interface diagnostic differences. Graphical

Language: Английский

Citations

9
A unified framework for estimating country-specific cumulative incidence for 18 diseases stratified by polygenic risk DOI Creative Commons
Bradley Jermy, Kristi Läll, Brooke N. Wolford

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 12, 2024

Abstract Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across life course; a key benefit over short-term prediction models. To produce estimates relevant clinical and public health decision-making, it is important account varying effects due age sex. Here, we develop novel framework estimate country-, age-, sex-specific of cumulative incidence stratified by PGS 18 high-burden diseases. We integrate associations from seven studies in four countries ( N = 1,197,129) with disease incidences Global Burden Disease. has significant effect asthma, hip osteoarthritis, gout, coronary heart type 2 diabetes (T2D), all but T2D exhibiting larger men. younger individuals 13 diseases, decreasing linearly age. show breast cancer that, relative bottom 20% polygenic risk, top 5% attain an absolute screening eligibility 16.3 years earlier. Our increases generalizability results biobank accuracy appropriately accounting age- effects. highlight potential as tool which may assist early prevention common

Language: Английский

Citations

9