A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies

Nature Methods, Год журнала: 2022, Номер 19(12), С. 1599 - 1611

Опубликована: Окт. 27, 2022

Язык: Английский

---

A method to estimate the contribution of rare coding variants to complex trait heritability

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

Опубликована: Фев. 9, 2024

Abstract It has been postulated that rare coding variants (RVs; MAF < 0.01) contribute to the “missing” heritability of complex traits. We developed a framework, Rare variant (RARity) estimator, assess RV ( h 2 ) without assuming particular genetic architecture. applied RARity 31 traits in UK Biobank n = 167,348) and showed gene-level aggregation suffers from 79% (95% CI: 68-93%) loss . Using unaggregated variants, 27 had > 5%, with height having highest at 21.9% 19.0-24.8%). The total heritability, including common recovered pedigree-based estimates for 11 can estimate , enabling assessment characteristics revealing 11, previously unreported, gene-phenotype relationships. Finally, we demonstrated silico pathogenicity prediction (variant-level) annotations do not generally enrich RVs over-contribute trait variance, thus, innovative methods are needed predict functionality.

Язык: Английский

---

Unravelling the genetic architecture of human complex traits through whole genome sequencing

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

Опубликована: Июнь 14, 2023

Whole genome sequencing has enabled new insights into the genetic architecture of complex traits, especially through access to low-frequency and rare variation. This Comment highlights key contributions from this technology discusses considerations for its use future perspectives.

Язык: Английский

---

The Use of Genetics for Reaching a Diagnosis in XY DSD

Sexual Development, Год журнала: 2022, Номер 16(2-3), С. 207 - 224

Опубликована: Янв. 1, 2022

Reaching a firm diagnosis is vital for the long-term management of patient with difference or disorder sex development (DSD). This especially case in XY DSD where diagnostic yield particularly low. Molecular genetic technology playing an increasingly important role process, and it highly likely that will be used more often at earlier stage process. In many cases DSD, clinical utility molecular genetics unequivocally clear, but other there need careful exploration benefit through monitoring these cases. Furthermore, incorporation into process requires appreciation strengths weaknesses evolving technology, interpretation results clear understanding wide range conditions are associated DSD.

Язык: Английский

---

Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population

Communications Biology, Год журнала: 2021, Номер 4(1)

Опубликована: Май 3, 2021

Abstract The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied the East-Asian population. Here we evaluated variants, including 1,915,154 Asian specific for leukocyte (LTL) associations among 25,533 Singapore Chinese samples. Three East in/near POT1 , TERF1 STN1 genes are LTL (Meta-analysis P 2.49×10 −14 –6.94×10 −10 ). Rs79314063, a missense variant (p.Asp410His) at shows effect 5.3 fold higher independent previous common index SNP. (rs79617270) (rs139620151) linked to LTL-associated SNPs these loci. Rs79617270 cancer mortality [HR 95%CI = 1.544 (1.173, 2.032), Adj 0.018] 4.76% association between rs79617270 colon mediated through LTL. Overall, genetically determined particularly lung adenocarcinoma 1.123 (1.051, 1.201), adj 0.007]. Ethnicity-specific may affect associate certain cancers.

Язык: Английский

---

Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study

The American Journal of Human Genetics, Год журнала: 2023, Номер 110(10), С. 1704 - 1717

Опубликована: Окт. 1, 2023

Язык: Английский

---

Non-coding rare variant associations with blood traits on 166 740 UK Biobank genomes

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 4, 2023

Abstract Large biobanks with whole-genome sequencing now enable the association of non-coding rare variants complex human traits. Given that >98% genome is available for exploration, selection remains a critical yet unresolved challenge in these analyses. Here, we leverage knowledge blood gene regulation and deleteriousness scores to select pertinent blood-related We whole 59 cell count biomarker measurements 166 740 UK Biobank samples perform variant collapsing tests. identified hundreds gene-trait associations involving across However, demonstrate majority (i) reproduce known from common studies (ii) are driven by linkage disequilibrium between nearby variants. This study underscores prevailing challenges analysis need caution when interpreting results.

Язык: Английский

---

Testing for association with rare variants in the coding and non-coding genome: RAVA-FIRST, a new approach based on CADD deleteriousness score

PLoS Genetics, Год журнала: 2022, Номер 18(9), С. e1009923 - e1009923

Опубликована: Сен. 16, 2022

Rare variant association tests (RVAT) have been developed to study the contribution of rare variants widely accessible through high-throughput sequencing technologies. RVAT require aggregate in testing units and filter retain only most likely causal ones. In exome, genes are natural usually filtered based on their functional consequences. However, when dealing with whole-genome sequence (WGS) data, both steps challenging. No biological unit is available for aggregating variants. Sliding windows procedures proposed circumvent this difficulty, however they blind information result a large number tests. We propose new strategy perform WGS data: "RAVA-FIRST" (RAre Variant Association using Functionally-InfoRmed STeps) comprising three steps. (1) New defined genome-wide functionally-adjusted Combined Annotation Dependent Depletion (CADD) scores observed gnomAD populations, which referred as "CADD regions". (2) A region-dependent filtering applied each CADD region. (3) functionally-informed burden test performed sub-scores computed genomic category within Both simulations real RAVA-FIRST was found outperform other WGS-based RVAT. Applied dataset venous thromboembolism patients, we identified an intergenic region chromosome 18 enriched early-onset patients. This that missed by standard sliding included TAD contains strong candidate gene. enables investigations non-coding complex diseases, facilitated its implementation R package Ravages.

Язык: Английский

---

Modeling transcriptional regulation using gene regulatory networks based on multi-omics data sources

BMC Bioinformatics, Год журнала: 2021, Номер 22(1)

Опубликована: Апрель 19, 2021

Transcriptional regulation is complex, requiring multiple cis (local) and trans acting mechanisms working in concert to drive gene expression, with disruption of these processes linked diseases. Previous computational attempts understand the influence regulatory on expression have used prediction models containing input features derived from factors. However, local chromatin looping trans-acting are known also transcriptional regulation, their inclusion may improve model accuracy interpretation. In this study, we create a general transcription factor by incorporating both features.We describe framework for GM12878 K562 cell lines. This weights impact factor-based data using multi-omics networks account mechanisms, measures context. These perform significantly better compared cis-regulatory alone. Models that additionally integrate long distance interactions (or looping) between distal binding regions promoters show improved accuracy. As demonstration utility, effect estimates were weight rare variants sequence kernel association test analyses expression.Our generate refined individual factors allowing characterization roles across genome. work provides integrating types into single regulation.

Язык: Английский

---

Integrating functional scoring and regulatory data to predict the effect of non-coding SNPs in a complex neurological disease

Briefings in Functional Genomics, Год журнала: 2023, Номер 23(2), С. 138 - 149

Опубликована: Май 30, 2023

Abstract Most SNPs associated with complex diseases seem to lie in non-coding regions of the genome; however, their contribution gene expression and disease phenotype remains poorly understood. Here, we established a workflow provide assistance prioritising functional relevance candidate genes as susceptibility loci polygenic neurological disorders. To illustrate applicability our workflow, considered multifactorial disorder migraine model follow step-by-step approach. We annotated overlap selected regulatory elements assessed potential impact on based publicly available prediction algorithms genomics information. Some risk have been hypothesised reside be implicated neurotransmission pathway. In this study, used set 22 from synaptic machinery-related previously suggested involved association studies. After these SNPs, focused non-reported ones that demonstrated high potential: (1) VAMP2_rs1150 (3′ UTR) was predicted target hsa-mir-5010-3p miRNA, possibly disrupting its own expression; (2) STX1A_rs6951030 (proximal enhancer) may affect binding affinity zinc-finger transcription factors (namely ZNF423) disturb TBL2 (3) SNAP25_rs2327264 (distal expected site ONECUT2 factor. This study practical facilitate prioritisation potentially relevant predict diseases.

Язык: Английский

---