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PubMed2026

Proteome-wide Mendelian randomisation of lung function to identify potential therapeutic targets for respiratory disease.

BACKGROUND: Despite multiple clinical trials, disease-modifying treatments for COPD are currently limited. Since many drugs target proteins, identifying causality between proteins and lung function informs understanding of COPD pathophysiology and may suggest novel targets. We used Mendelian randomisation (MR) to prioritise proteins as potentially causal for imparied lung function. For prioritised proteins, we explored their potential suitability as drug targets by predicting their effects on a range of clinical outcomes. METHODS: We used genome-wide association study (GWAS) data on 2923 proteins (n=48 195, UK Biobank) to identify single genetic variants (protein quantitative trait loci (cis-pQTLs)) associated with protein levels (p≤5×10-9, variant ≤100 kb of a transcription start site). We performed cis-pQTL-MR analyses of four spirometric traits (n=149 166, 36 independent cohorts). Sensitivity analyses included colocalisation and reverse direction MR. We report associations between cis-pQTLs for prioritised proteins and multiple clinical respiratory outcomes, and use phenome-wide analysis to explore potential adverse effects or drug repurposing opportunities. FINDINGS: 1841 proteins had a suitable cis-pQTL. We implicated 16 proteins as potentially causal for lung function (p<1.71×10-5): seven proteins have not been implicated by previous lung function GWAS or MR (CCND2, DTD1, PILRA, PTPRK, TDRKH, GRHPR, NUDT5), and we provide corroborative evidence for 10 proteins. We add to the literature identifying surfactant protein D (SFTPD) as a candidate, yet predict that integrin subunit alpha V (ITGAV) inhibition could impair some lung function measures, mimicking adverse results from a recent trial. INTERPRETATION: Our approach identifies proteins (some novel) that are potentially therapeutic targets for respiratory disease, and which warrant follow-up for utility and safety.

Journal Article↗

PubMed2006

Generation Scotland: the Scottish Family Health Study; a new resource for researching genes and heritability.

BACKGROUND: Generation Scotland: the Scottish Family Health Study aims to identify genetic variants accounting for variation in levels of quantitative traits underlying the major common complex diseases (such as cardiovascular disease, cognitive decline, mental illness) in Scotland. METHODS/DESIGN: Generation Scotland will recruit a family-based cohort of up to 50,000 individuals (comprising siblings and parent-offspring groups) across Scotland. It will be a six-year programme, beginning in Glasgow and Tayside in the first two years (Phase 1) before extending to other parts of Scotland in the remaining four years (Phase 2). In Phase 1, individuals aged between 35 and 55 years, living in the East and West of Scotland will be invited to participate, along with at least one (and preferably more) siblings and any other first degree relatives aged 18 or over. The total initial sample size will be 15,000 and it is planned that this will increase to 50,000 in Phase 2. All participants will be asked to contribute blood samples from which DNA will be extracted and stored for future investigation. The information from the DNA, along with answers to a life-style and medical history questionnaire, clinical and biochemical measurements taken at the time of donation, and subsequent health developments over the life course (traced through electronic health records) will be stored and used for research purposes. In addition, a detailed public consultation process will begin that will allow respondents' views to shape and develop the study. This is an important aspect to the research, and forms the continuation of a long-term parallel engagement process. DISCUSSION: As well as gene identification, the family-based study design will allow measurement of the heritability and familial aggregation of relevant quantitative traits, and the study of how genetic effects may vary by parent-of-origin. Long-term potential outcomes of this research include the targeting of disease prevention and treatment, and the development of screening tools based on the new genetic information. This study approach is complementary to other population-based genetic epidemiology studies, such as UK Biobank, which are established primarily to characterise genes and genetic risk in the population.

Adolescent↗

PubMed2006

PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease.

We analysed relationships between the PTPN22 1858 polymorphism and antibodies to cyclic citrullinated peptide (CCP), rheumatoid factors (RFs) and the shared epitope (SE) gene (HLA-DRB1*0404 or 0401) and determined their combined predictive value for rheumatoid arthritis (RA) in individuals who subsequently developed RA. This case-control study was nested within the Medical Biobank of Northern Sweden. Patients with RA (n = 92) were identified from amongst blood donors antedating onset of disease by a median of 2.4 (interquartile range 1.2 to 4.9) years. Matched controls were selected randomly from the same cohorts (n = 368). Anti-CCP antibodies and RFs were determined using enzyme-linked immunoassays. Genotyping was performed using an ABI PRISM 7900HT instrument and HLA-SE genes were identified using PCR sequence-specific primers. The 1858T allele and also carriage of T were associated with future onset of RA (odds ratio (OR) = 2.29, 95% confidence interval (CI) 1.45-3.61 and OR = 2.64, 95% CI 1.56-4.47, respectively). The combination of the 1858T variant and anti-CCP antibodies gave 100% specificity for the disease. None of the 368 controls expressed this combination. The PTPN22 1858T variant and anti-CCP antibodies were clearly associated (OR = 3.80, 95% CI 1.51-9.57). A combination of the PTPN22 1858T variant and anti-CCP antibodies gave a much higher relative risk (>132.03) for developing RA than the combination of the T variant and HLA-SE (OR = 7.85). The PTPN22 1858T variant was associated with future development of RA. There was an association between the T variant and anti-CCP antibodies and their combination, found only among pre-patients, gives a very high relative risk for development of RA. The combination gave a specificity of 100% for diagnosing RA.

Arthritis, Rheumatoid↗

PubMed2025

A genome-wide association study identifies a novel East Asian-specific locus for dementia with Lewy bodies in Japanese subjects.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia in older patients. As with other multifactorial diseases, the pathogenesis results from interactions of environmental and genetic factors. The genetic basis of DLB is not yet fully understood. Recent genomic analyses of DLB in Caucasian cohorts identified genetic susceptibility loci for DLB, but the comprehensive genomic analysis in Asians was still not performed. METHODS: We conducted a genome-wide association study (GWAS) in Japanese subjects (211 DLB cases and 6113 controls) to clarify the genetic architecture of DLB pathogenesis. RESULTS: We identified the East Asian-specific DHTKD1 locus (rs138587229) on chromosome 10 with genome-wide significance (GWS; P = 3.2710-8) and the ICOS/PARD3B locus on chromosome 2 with suggestive significance (P = 3.9510-7) as novel DLB genetic risk loci. We also confirmed the APOE locus (rs429358, P < 5.0 × 10-8), a known risk locus for DLB and Alzheimer's disease in Caucasians. The DHTKD1 locus was associated with the gene expression of SEC61A2 and showed a causal relationship with cholinesterase levels. In a trans-ethnic meta-analysis that included Japanese, UK Biobank, and other Caucasian GWAS, we confirmed the risk for DLB at APOE and SNCA loci with GWS. Transcriptome-wide association analysis identified ZNF155 and ZNF284 in the brain cortex and GPRIN3 in the substantia nigra as putative causal genes for DLB. CONCLUSIONS: This is the first GWAS for DLB in East Asians, and our findings provide new biological and clinical insights into the pathogenesis of DLB.

Aged↗

PubMed2026

Associations of genetically predicted interleukin-6 and tumor necrosis factor signaling pathways with mortality among persons with colorectal cancer: a two-sample Mendelian randomization.

BACKGROUND: Despite significant progress in identifying risk factors for colorectal cancer (CRC), factors influencing survival in people with CRC remain less understood. Pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been implicated in cancer progression and may influence CRC outcomes. We investigated associations between genetically predicted levels of IL-6 and TNF-α signaling pathways and mortality in people with CRC. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using cis-acting single nucleotide polymorphisms (SNPs) associated with soluble IL-6 receptor alpha (sIL6-RA) and IL-6 signal transducer gp130 (IL6ST), representing IL-6 signaling, and with TNF-α, and its soluble receptors (sTNF-R1, sTNF-R2). SNPs were obtained separately from two large genome-wide association studies (GWAS): deCODE and UK Biobank (UKB). The outcome was CRC-specific mortality among 16,964 CRC cases (4010 deaths) in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Analyses were stratified by tumor site and stage. The inverse variance weighted (IVW) method, incorporating a correlation matrix for dependent SNPs, was used for primary analyses. Because literature links TNF-α to CRC incidence, we additionally performed a simulation study to evaluate the potential impact of collider bias resulting from restricting analyses to CRC cases. RESULTS: Genetically predicted sIL6-RA was weakly positively associated with CRC-specific mortality (deCODE-SNPs (n = 13) HR per 1 SD increase: 1.06; 95% CI: 1.00-1.12; UKB-SNPs (n = 11) HR: 1.09; 95% CI: 1.02-1.17). Genetically proxied IL6ST levels showed no association with CRC-specific mortality in the overall sample (deCODE-SNPs (n = 19) HR: 1.04; 95% CI: 0.90-1.21; UKB-SNPs (n = 9) HR: 1.11; 95% CI: 0.87-2.42), while higher IL6ST levels were associated with increased mortality among patients with stage 2/3 disease (deCODE-SNPs (n = 19) HR: 1.45; 95% CI: 1.10-1.91; UKB-SNPs (n = 9) HR: 1.87; 95% CI: 1.22-2.89). No associations were observed for TNF-α, sTNF-R1, or sTNF-R2. Findings for all exposures were consistent across both GWAS datasets. Simulation analyses for TNF-α indicated collider bias was present but limited in magnitude. CONCLUSIONS: Our findings suggest that IL-6 signaling may play a role in CRC progression although of limited magnitude, whereas TNF-related pathways appear less relevant for prognosis.

Humans↗

PubMed2026

The association between GLP-1R expression and cardiovascular-kidney-metabolic-related diseases in non-diabetic and non-obese population: evidence triangulation using Mendelian randomization, observational and polygenic score association analysis.

BACKGROUND: Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging as promising therapies for cardiovascular-kidney-metabolic (CKM) related diseases in individuals with type 2 diabetes mellitus (T2DM) or obesity. But their effects in non-obese and non-diabetic individuals are unclear. This study triangulates evidence using Mendelian randomization (MR), polygenic scores (PGS) and observational analyses to estimate the associations of GLP-1R expression with chronic kidney disease (CKD), heart failure (HF) and metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: For the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (N ≤ 305). MR-Robust method was used as the primary MR approach. PGS and observational analyses were performed both in non-diabetic and non-obese individuals separately. A genome-wide association study (GWAS) for MASLD (14,231 cases and 348,091 controls) was performed in the general population using data from UK Biobank. RESULTS: GLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95%CI 0.95 to 0.97, q = 1.7 × 10- 10 ), HF (OR = 0.96, 95%CI 0.94 to 0.97, q = 2.5 × 10- 8) and MASLD (OR = 0.96, 95%CI 0.93 to 0.98, q = 1.3 × 10- 3) in the general population. Consistent results were observed in validation analyses. Furthermore, PGS and observational analyses among non-T2DM and non-obese individuals found little evidence to support its association with CKD, HF or MASLD. GWAS analysis identified eight conditionally independent variants associated with MASLD, in which rs563199662 was a new signal located at TFPI region. CONCLUSIONS: This study provides multilayered evidence for GLP-1R expression in mitigating CKD, HF and MASLD risks in the general population, while de-prioritized its effect on CKM-related diseases in non-obese and non-diabetic individuals. Further clinical trials are needed to validate the effects of GLP-1R agonists in relative health population.

Humans↗

PubMed2025

Causal relationship between educational attainment and the occurrence of venous thromboembolism.

BACKGROUND: The association between educational attainment (EA) and arterial thrombotic disease has been reported, but the causal relationship between EA and venous thromboembolism (VTE) is not clear. We aimed to assess the causal effect of EA on VTE using the two-sample mendelian randomization (MR) method. METHODS: Data mining was conducted on the genome wide association studies (GWAS), with exposure factor EA and outcome factor VTE. Two-sample Mendelian Randomization (TSMR) analysis was conducted, with the results obtained from the random effects inverse variance weighted method (IVW). Use the MR-Egger method for pleiotropy analysis and leave one method for sensitivity analysis to verify the reliability of the data. RESULTS: Genetically predicted decreased EA was associated with a decreased risk of VTE in both the FinnGen consortium and UK Biobank (FinnGen-VTE: OR = 0.848; 95% CI 0.776-0.927; P = 2.84 × 10-4; UKB-VTE OR = 0.996; 95% CI 0.994-0.999; P = 0.008) under a multiplicative random-effects IVW model. Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. CONCLUSIONS: The MR technique instructed a potential inverse causative relationship between EA and occurrence of VTE. Therefore, patients with low EA should be more vigilant about the occurrence of VTE.

Venous Thromboembolism↗

PubMed2025

Severe traumatic brain injury and risk for osteoporosis: a Mendelian randomization study.

BACKGROUND: The influence of nervous system activity on bone remodeling has been widely reported. Patients with traumatic brain injury (TBI) exhibit a high incidence of osteoporosis (OP). Nevertheless, the relationship between severe TBI (sTBI) and OP remains unclear. We performed Mendelian randomization (MR) analysis to assess the potential causal relationship between sTBI and OP. METHODS: Data on exposure and outcomes were acquired from genome-wide association studies (GWAS). Data on OP was obtained from UK Biobank (5,266 cases of OP and 331,893 controls). Data on sTBI was obtained from FinnGen Consortium (6,687 cases and 370,590 controls). Single nucleotide polymorphisms (SNPs) that underwent strict screening were regarded as instrumental variables. We used the inverse variance weighted (IVW), constrained maximum likelihood and model averaging (CML-MA), MR-Egger, and weighted median methods for causal effect estimation. To test the reliability of the results, sensitivity analysis was performed using Cochran's Q, leave-one-out, MR-Egger intercept, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) tests. RESULTS: The IVW analysis indicates that sTBI and OP have a suggestive association (odds ratio [OR] = 1.004, 95% confidence interval [CI] = 1.001,1.007; p = 0.002), and no heterogeneity (Q = 11.536, p = 0.241) or directional pleiotropy was observed (egger_intercept = 7.368 × 10- 5, p = 0.870). The robustness of the results was validated using a leave-one-out sensitivity test. CONCLUSION: According to the MR analysis, sTBI and OP are likely suggestively related. This finding contributes to the prevention of OP in patients with sTBI and provides genetic evidence supporting the theory that the nervous system regulates bone remodeling.

Humans↗

PubMed2025

Causal association between non-steroidal anti-inflammatory drugs use and the risk of benign prostatic hyperplasia: a univariable and multivariable Mendelian randomization study.

BACKGROUND: The results of earlier observational research on the relationships between the usage of non-steroidal anti-inflammatory medicines (NSAIDs) and the risk of benign prostatic hyperplasia (BPH) have been inconsistent. METHODS: To assess these associations, we performed both univariable and multivariable Mendelian randomization (MR) studies. Instrumental variables (IVs) associated with exposures at the significance level (p < 5 × 10-6) were selected from a comprehensive meta-analysis conducted by the United Kingdom Biobank (UKB). Summary data for BPH were obtained from the FinnGen consortium, which comprised 30,066 cases and 119,297 controls. Sensitivity analyses were performed to evaluate heterogeneity and pleiotropy. RESULTS: We found evidence by univariable MR (UVMR) that genetically predicted NSAIDs use increased the risk of BPH (odds ratio [OR] per unit increase in log odds NSAIDs use: 1.164, 95% confidence interval [CI]: 1.041-1.302, p = 0.008). After controlling for inflammation in multivariable MR (MVMR), the link persisted (OR: 1.165, 95% CI: 1.049-1.293, p = 0.004). There were no indications of potential heterogeneity and pleiotropy in UVMR and MVMR analyses. CONCLUSION: The results of the MR estimates suggest that genetically predicted NSAIDs use may elevate the risk of BPH. This outcome prompts the imperative for deeper exploration into potential underlying mechanisms.

Humans↗

PubMed2025

Predicting breast cancer risk and its association to biopsychosocial factors among Taiwanese women with a family history of breast cancer: an investigation based on the Gail model.

BACKGROUND: First-degree relatives with breast cancer have a two-fold higher risk than women without a family history. The Gail model approach has been employed in numerous studies to investigate the risk of breast cancer among women in a variety of countries. Nevertheless, the studies investigating the correlation between the level of breast cancer risk and biopsychosocial factors among Taiwanese women with a family history of breast cancer (FHBC) are limited. By using the Gail model, we explored the breast cancer risk score and its relationship to biopsychosocial factors among Taiwanese women with FHBC. METHODS: The present study was a cross-sectional study from secondary data of the Taiwan Biobank from 2008 to 2018. Self-reports were conducted to determine biopsychosocial factors. A total of 3,060 women aged 35-70 years with and without FHBC were considered eligible for enrollment. The Gail model, which utilizes six questions, was used to estimate individual five-year absolute breast cancer risk. Women with scores at least 1.66% and above were categorized as high risk. In addition, we performed bivariate and multivariate logistic regression analysis using SPSS version 27 to predict the associations between biopsychosocial factors and the risk of breast cancer based on the Gail model. All analyses were stratified by age. RESULTS: Among the 3,060 Taiwanese women, there was a statistically significant difference in breast cancer risk score between the groups with and without FHBC (p = < 0.001), stratified by age, of which 574 in FHBC group (34.2%) were identified as having a high breast cancer risk based on the Gail model. Furthermore, six out of 15 biopsychosocial factors were significantly associated with breast cancer risk in women under 50 years of age, while seven factors showed significant associations in women aged 50 years and older. Logistic regression analysis identified five biopsychosocial factors as consistent and significant predictors of breast cancer risk in women aged 50 years and older, highlighting this group as particularly vulnerable. CONCLUSIONS: This study concludes that the Gail model identifies Taiwanese women who have a higher estimated risk of breast cancer based on cross-sectional data. Various biopsychosocial factors are associated with higher risk estimates in this population particularly in older women. Professionals can assist women in recognizing risk factors beyond the inevitable risk by encouraging regular screenings, positive behavior, and health promotion.

Humans↗

PubMed2026

Drug targets for lipid modification and risk of type 2 diabetes: a cis-Mendelian randomization study.

BACKGROUND AND AIMS: Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) is the cornerstone in the prevention of coronary artery disease (CAD) but may also increase risk of type 2 diabetes (T2D). A comprehensive examination of the genetic evidence of T2D related side-effects of all current lipid-modifying drugs, including those in development, has not yet been performed. METHODS: This cis-Mendelian randomization study used individual level data from the UK Biobank, Lifelines, and publicly available genome-wide association data. We identified loci that are either targeted directly with drugs, or alternatively, targeting their gene products (mRNA and/or protein). Included are, in alphabetical order, the loci ACLY, ANGPTL3, ANGPTL4, APOB, APOC3, CETP, HMGCR, LDLR, LIPG, LPA, MTTP, NPC1L1, and PCSK9. We used cis-genetic instruments weighted for LDL-C, HDL-C, triglycerides, and apolipoproteins as downstream proxies for the drug targets. Main outcomes were prevalent and incident T2D, with CAD as a contrast outcome. RESULTS: Lipid modification through HMGCR is predicted to reduce CAD risk and increase T2D risk. Modification through targeting APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 is predicted to reduce CAD risk without a change in T2D risk. Modification through ANGPTL4 and CETP is predicted to reduce risk of both CAD and T2D. For ACLY, ANGPTL3, APOB, and LIPG, we found evidence for neither CAD nor T2D. CONCLUSIONS: This study provides genetic evidence for variation in diabetes-related side-effects of different lipid-modifying drugs, with potential relevance for future clinical trials and individual treatment decisions.

Humans↗

PubMed2026

Cell type resolved MR based on brain single cell eQTLs corroborated by single cell RNA sequencing uncovers neuroimmune and vascular programs in intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) lacks effective neuroprotective therapies. We integrated cell type–resolved genetic inference with single-cell profiling to map putative causal programs and multicellular circuitry relevant to ICH. METHODS: Cis-eQTLs from eight human brain cell types were used as instruments for two-sample Mendelian randomization (MR), with an ICH meta-analysis from large biobanks and a stroke consortium as the outcome. Instruments were LD-pruned and restricted to strong variants (F > 10). Inverse-variance weighting (IVW) was the primary estimator, supported by robustness methods, heterogeneity/pleiotropy diagnostics, and false discovery rate control. Experimental validation used mouse collagenase ICH single-cell RNA-seq at 24 h (n = 3 sham; n = 3 ICH) with Seurat integration, composition testing, Slingshot pseudotime, and CellChat. An independent mouse cohort underwent qRT–PCR for selected genes. RESULTS: The ICH meta-analysis showed acceptable genomic control, supporting downstream MR. We identified 524 nominal gene–cell type associations, with a glia-weighted signal landscape. Enrichment implicated autophagy/mitophagy, antigen processing, cytoskeletal and vesicular trafficking, endothelial matrix–adhesion programs, ferroptosis, and myelin stress pathways. In mouse scRNA-seq, disease-associated microglia expanded with reciprocal loss of homeostatic microglia and increased neutrophils and T cells. Prioritized genes showed directional concordance; qRT–PCR confirmed ARPC3 and EIF2AK2 upregulation and TBCK and SPECC1 downregulation in ICH versus sham. Pseudotime supported a shift toward disease-associated microglial states, and CellChat indicated increased network interaction strength with microglia and endothelium as hubs. CONCLUSIONS: Cell type–specific MR combined with single-cell validation highlights neuroimmune and neurovascular programs in ICH and links genetic signals to state transitions and inferred intercellular communication.

Animals↗

PubMed2026

An immune-associated mitochondrial DNA variant with sex differences reveals a putative novel microprotein called MASL.

The use of mitochondrial wide association studies (MiWAS) to link mitochondrial DNA variants (mtSNPs) to phenotypes of interest has uncovered important connections between mitochondrial genes and human health. The recent introduction of a re-annotated mitochondrial genome that accounts for small open reading frames (sORFs) with protein coding potential suggests the existence of mitochondrial-derived microproteins, many of which remain uncharacterized. Thus, considering the re-annotated mitochondrial genome when conducting genomic analyses such as MiWAS facilitates the mapping of mtSNPs back to microprotein-encoding sORFs and uncovers interactions between mitochondrial microproteins and biological systems. Here, we employ MiWAS of venous blood samples from the Health and Retirement Study (HRS) and identify a mtSNP associated with sex-specific changes to immune composition. After accounting for re-annotation, we map the identified mtSNP back to a sORF that encodes a novel microprotein, termed MASL (Mitochondrial Associated Small d-Loop peptide). Complementary phenome-wide association studies (PheWAS) in HRS and and UK Biobank confirm interactions between this mtSNP and immune phenotypes of interest, and our targeted RNA-Seq method (mitoSNP-seq) elucidates sex-differences in gene expression and functional pathways potentially altered by this mtSNP that may be relevant to the associated microprotein. Early characterization of the MASL microprotein shows sex-differences in circulating MASL levels in human plasma, and sex-specific interactions when comparing male and female mice treated with synthesized MASL. Together, the results of this study not only contribute to our understanding of mitochondrial dynamics in immunity, but also provide early characterization of a novel mitochondrial-derived microprotein with sex-specific modulatory effects.

Genomics↗

PubMed2025

Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.

BACKGROUND: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability. RESULTS: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate. CONCLUSIONS: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.

Humans↗

PubMed2026

Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.

BACKGROUND: Tandem repeat expansions have been implicated in various neurological conditions. Here, we present a novel hypermethylated CCG repeat expansion on Xp22 in the 5'UTR of BCLAF3 in males with neurodevelopmental disorders. METHODS: We used patient-derived fibroblasts and neuronal models from a family with BCLAF3 repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with BCLAF3 repeat expansions, we screened methylation arrays (n = 12,375) and short-read genomes (n = 15,963) from probands with neurodevelopmental presentations. We also characterized BCLAF3 repeat expansions in the general population using long-read sequencing data (n = 793) and population-level short-read sequencing data (n = 410,076). RESULTS: Long-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed BCLAF3 RNA and protein expression. We show that the BCLAF3 CCG repeat expansion constitutes a previously uncharacterized fragile site (FRAXG) that shifts the surrounding chromatin compartment from open euchromatin to closed heterochromatin. Using our multiomic screening approaches, we identified three additional unrelated males and one related male cousin with long-read sequencing validated (n = 2) or short-read sequencing predicted (n = 2) repeat expansions. In one family, the BCLAF3 repeats segregate with more severe phenotypes than expected for the primary diagnoses. Long-read sequencing in three carrier mothers showed skewed X-inactivation against the repeat expansion, highlighting the potential deleterious effect of an allele with an expansion. Expansions were absent in long-read sequencing data from control populations. Assessment of the BCLAF3 repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than FMR1 repeat expansions. CONCLUSIONS: CCG repeat expansions in the 5'UTR of BCLAF3 likely constitute a novel genetic etiology associated with X-linked neurodevelopmental phenotypes in males. Future work will be essential to delineate the phenotypic spectrum and determine a disease pathomechanism.

BCLAF3↗

PubMed2022

Temporal associations between leukocytes DNA methylation and blood lipids: a longitudinal study.

BACKGROUND: The associations between blood lipids and DNA methylation have been investigated in epigenome-wide association studies mainly among European ancestry populations. Several studies have explored the direction of the association using cross-sectional data, while evidence of longitudinal data is still lacking. RESULTS: We tested the associations between peripheral blood leukocytes DNA methylation and four lipid measures from Illumina 450 K or EPIC arrays in 1084 participants from the Chinese National Twin Registry and replicated the result in 988 participants from the China Kadoorie Biobank. A total of 23 associations of 19 CpG sites were identified, with 4 CpG sites located in or adjacent to 3 genes (TMEM49, SNX5/SNORD17 and CCDC7) being novel. Among the validated associations, we conducted a cross-lagged analysis to explore the temporal sequence and found temporal associations of methylation levels of 2 CpG sites with triglyceride and 2 CpG sites with high-density lipoprotein-cholesterol (HDL-C) in all twins. In addition, methylation levels of cg11024682 located in SREBF1 at baseline were temporally associated with triglyceride at follow-up in only monozygotic twins. We then performed a mediation analysis with the longitudinal data and the result showed that the association between body mass index and HDL-C was partially mediated by the methylation level of cg06500161 (ABCG1), with a mediation proportion of 10.1%. CONCLUSIONS: Our study indicated that the DNA methylation levels of ABCG1, AKAP1 and SREBF1 may be involved in lipid metabolism and provided evidence for elucidating the regulatory mechanism of lipid homeostasis.

Humans↗

PubMed2025

Carrying APOL1 G1 allele is associated with cardiovascular complications during COVID-19 in an admixed population.

BACKGROUND: The APOL1 G1 and G2 alleles were selected in the Sub-Saharan African population by conferring resistance to trypanosome infection. However, these alleles are associated with kidney diseases, and their role in cardiovascular complications remains uncertain. A second hit mediated by an inflammatory state is necessary for APOL1-mediated phenotypes. Thus, this cross-sectional study investigates the association of APOL1 alleles with COVID-19 outcomes such as cardiovascular complications and kidney injury in an admixed population. Whole-genome sequencing was performed for 485 patients with different outcomes from a Biobank in Southern Brazil. RESULTS: COVID-19 individuals presented median age of 51 years, 281 were hospitalized, and 10.9% had CKD previous to the infection. Global ancestry inference revealed 12.8% of African ancestry. The G1 allele frequency was 2.7% and G2 allele was 1.2%. Local ancestry inference evidenced African ancestry in the locus of APOL1 alleles. The G1 allele frequency was higher among patients with severe outcomes. The presence of this allele was associated with kidney injury (OR = 2.78; 95% CI = 1.04-7.42; p = 0.041) using a minimally adjusted model and cardiovascular complications with a minimally (OR = 4.61; 95% CI = 1.61-13.19; p = 0.004) and fully adjusted model (OR = 4.59; 95% CI = 1.41-14.96; p = 0.011). Four individuals carried two alleles (three G1/G1 and one G1/G2) and three of them progressed to severe COVID-19 developing kidney injury. CONCLUSION: APOL1 risk alleles are present in the Brazilian population due to genetic admixture and the G1 allele was associated with COVID-19 outcomes.

Humans↗

PubMed2025

Association of Genetic Predisposition to Inflammation With Cancer-Related Cognitive Impairment and Fatigue in Women Who Received Chemotherapy for Nonmetastatic Breast Cancer.

PURPOSE: Cancer-related cognitive impairment (CRCI) and cancer-related fatigue (CRF) are reported by approximately 75% of patients receiving chemotherapy for breast cancer and both have been linked to inflammation. We sought to test whether an inflammation polygenic risk score (iPRS) might be associated with CRCI and/or CRF. METHODS: Using data from the UK Biobank, we developed an iPRS for the INFLA-Score, a composite measure of C-reactive protein, white cell count, platelet count, and neutrophil-lymphocyte ratio. The iPRS was evaluated for association with CRCI and CRF among women with nonmetastatic breast cancer enrolled in two completed multisite clinical trials: URCC08106 and URCC10055. CRCI and CRF were measured before and after standard-of-care chemotherapy using the FACT-Cog and Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), respectively. Linear regression evaluated the change in FACT-Cog and MFSI scores; logistic regression evaluated binary outcomes of any versus no worsening of scores. Analyses were adjusted for patient and treatment factors. We also performed exploratory genome-wide analyses. RESULTS: The cohort included 802 women who received chemotherapy (anthracycline-based = 51.8%; previous surgery = 85.0%) at a median age of 55 years (range = 22-81). The iPRS was associated with a significant decrease in MFSI-SF score (β = -3.29 [95% CI, -6.25 to -0.34]; P = .029) and lower odds of decreased MFSI-SF score (odds ratio, 0.66 [95% CI, 0.47 to 0.93]; P = .016) following chemotherapy. This negative relationship was partially explained by a positive correlation of the iPRS with prechemotherapy MFSI-SF score (β = 4.33 [95% CI, 0.23 to 8.43]; P = .038). The iPRS was not associated with a change in FACT-Cog score (β = -1.12; P = .627), but single nucleotide polymorphism rs9365961 was (β = -10.05; P = 1.46 × 10-8). CONCLUSION: If validated, the iPRS could identify patients in need of supportive care interventions to reduce CRF.

Humans↗