Rare copy-number variants as modulators of common disease susceptibility

Genome Medicine, Год журнала: 2024, Номер 16(1)

Опубликована: Янв. 8, 2024

Copy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life the general population remains poorly described.

Язык: Английский

---

Breaking down causes, consequences, and mediating effects of telomere length variation on human health

Genome biology, Год журнала: 2024, Номер 25(1)

Опубликована: Май 17, 2024

Abstract Background Telomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants European ancestry. Results Using linear regression bidirectional univariable multivariable Mendelian randomization (MR), elucidate relationships between leukocyte length (LTL) 142 complex traits, including diseases, biomarkers, lifestyle factors. We confirm that telomeres age show a stronger decline in males than females, these contributing to majority 5.4% LTL variance explained by phenome. MR reveals 23 traits LTL. Smoking cessation high educational attainment associate longer LTL, while weekly alcohol intake, body mass index, urate levels, female reproductive events, such as childbirth, shorter also identify 24 affected risk for cardiovascular, pulmonary, some autoimmune diseases being increased short other conditions cancers. Through MR, may partially mediate impact attainment, childbirth on proxied lifespan. Conclusions Our study sheds light modulators, consequences, mediatory role telomeres, portraying an intricate relationship lifestyle, socio-economic

Язык: Английский

---

Genome-wide association testing beyond SNPs

Nature Reviews Genetics, Год журнала: 2024, Номер unknown

Опубликована: Окт. 7, 2024

Язык: Английский

---

Potential link between copy number variation and abnormal genome wide DNA methylation profile in an individual with severe ADHD and a strong response to micronutrient treatment

Psychiatry Research Case Reports, Год журнала: 2025, Номер unknown, С. 100254 - 100254

Опубликована: Фев. 1, 2025

Язык: Английский

---

Gene dosage architecture across complex traits

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 26, 2025

Copy number variants (CNVs) have large effects on complex traits, but they are rare and remain challenging to study. As a result, our understanding of biological functions linking gene dosage traits remains limited, whether these sensitive similar those underlying the single nucleotide (SNVs) common unknown. We developed FunBurd, functional burden analysis, test association CNVs aggregated within sets. applied this approach in 500,000 individuals from UK Biobank associate 43 with disrupting 172 sets across tissues cell types. compared CNV findings LoF (Loss Function) SNVs same cohort using All showed FDR significant associations CNVs. Brain tissue neuronal cell-types highest levels pleiotropy. Most set could, part, be explained by genetic constraint, except for brain related processes. Shared contributions between pairs were concordant types variants, average 2-fold higher, variants.Functional enrichment found limited overlap variants. Moreover, deletions duplications negatively correlated most traits.In conclusion, we present new methods separate constraint function traits. Overall, convergence different -even duplications- limited. limited.FunBurd (functional analysis) was UKBiobank tissues/cell type sets.All brain-related higher The Our provide insights

Язык: Английский

---

Lessons from national biobank projects utilizing whole-genome sequencing for population-scale genomics

Genomics & Informatics, Год журнала: 2025, Номер 23(1)

Опубликована: Март 6, 2025

Large-scale national biobank projects utilizing whole-genome sequencing have emerged as transformative resources for understanding human genetic variation and its relationship to health disease. These initiatives, which include the UK Biobank, All of Us Research Program, Singapore's PRECISE, Biobank Japan, National Project Bio-Big Data Korea, are generating unprecedented volumes high-resolution genomic data integrated with comprehensive phenotypic, environmental, clinical information. This review examines methodologies, contributions, challenges major WGS-based genome worldwide. We first discuss landscape highlighting their distinct approaches collection, participant recruitment, phenotype characterization. then introduce recent technological advances that enable efficient processing analysis large-scale WGS data, including improvements in variant calling algorithms, innovative methods creating multi-sample VCFs, optimized storage formats, cloud-based computing solutions. The synthesizes key discoveries from these projects, particularly identifying expression quantitative trait loci rare variants associated complex diseases. Our introduces latest findings has advanced our population-specific diseases Korean East Asian populations. Finally, we future directions maximizing impact on precision medicine global equity. examination demonstrates how revolutionizing research healthcare delivery while importance continued investment diverse, resources.

Язык: Английский

---

Longitudinal Genome-Wide Study Reveals Genetic Architecture of Resilience Using a Novel Phenotype

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 19, 2025

The biological mechanisms underlying resilience have been extensively studied, yet our understanding of the genetic architecture in humans remains limited. While earlier studies investigated effects specific candidate genes, small sample sizes and narrow focus on one target gene provided a limited perspective architecture. Genome-wide association (GWAS) can overcome these issues but rarely applied to resilience. To date, only two GWAS are reported, because few sufficiently large-scale datasets measure resilience, those that do may not data. Here we used novel longitudinal phenotype with genomic data from Avon Longitudinal Study Parent Children (ALSPAC) establish trajectories response adverse childhood experiences (ACEs). Our results identify SMARCA2 OPRM1 genes as significant markers, highlighting their roles epigenetic dendritic functions associated Post-GWAS analyses revealed enrichment linked axonal functions, supporting hypothesis spine plasticity is crucial for cognitive approach offers functional insights into how across early life underpinned by factors, emphasising importance dynamic, phenotyping.

Язык: Английский

---

Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs

The American Journal of Human Genetics, Год журнала: 2024, Номер 111(11), С. 2347 - 2361

Опубликована: Сен. 26, 2024

Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies genomic syndromes in both clinical and population cohorts, mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between region's copy number 117 complex traits diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by CNVs, with deletion-only, mirror, U-shape, duplication-only models being best fit for 30, 10, 4, 2 phenotypes, respectively, aligning stronger deleteriousness deletion. Upon individually adjusting CNV effects either body mass index (BMI), height, or educational attainment (EA), found that sixteen testable deletion-driven associations-primarily cardiovascular metabolic traits-were BMI dependent, EA playing more subtle role no depending on height. Bidirectional Mendelian randomization supported 13 out these 16 associations secondary consequences CNV's impact BMI. For 23 remained significantly associated upon individual adjustment mediators, matched-control analyses 10 including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, pneumonia acute kidney injury risk, under strict Bonferroni correction, additional nominally significant associations. These results paint picture BP4-5's pattern involves direct multiple physiological systems indirect co-morbidities consequential EA, acting through trait-specific mechanisms.

Язык: Английский

---

The pleiotropic spectrum of proximal 16p11.2 CNVs

The American Journal of Human Genetics, Год журнала: 2024, Номер unknown

Опубликована: Сен. 1, 2024

Язык: Английский

---

Evaluation of the Copy Number Variants and Single-Nucleotide Polymorphisms of ABCA3 in Newborns with Respiratory Distress Syndrome—A Pilot Study

Medicina, Год журнала: 2024, Номер 60(3), С. 419 - 419

Опубликована: Фев. 29, 2024

Background and Objectives: Respiratory distress syndrome (RDS) in preterm infants commonly occurs due to the immaturity-related deficiency of pulmonary surfactant. Beyond prematurity, various environmental genetic factors can influence onset progression RDS. This study aimed analyze three single-nucleotide polymorphisms (SNPs) ABCA3 gene assess as a candidate for susceptibility RDS overall survival newborns evaluate utility MLPA neonatal patients. Materials Methods: Three SNPs were chosen genotyped cohort 304 newborns. Data analysis statistical tests employed examine allele frequencies, haplotypes, measures pairwise linkage disequilibrium. Results: There was no observed haplotype association with rs13332514 (c.1059G>A) rs170447 (c.1741+33T>C) among newborns, both without (p > 0.05). The minor C frequency rs323043 (c.1755G>C) SNP showed significant increase results indicated that predominant findings normal, revealing CNVs genes SFTPC investigated our Conclusions: presence variant may be risk factor premature

Язык: Английский

---