Biology subjects

FinnGen,

Publications and source records attributed to FinnGen,.

12 recordsLinked to original sources

bioRxiv2026

Intergenerational instability of the C9orf72 hexanucleotide repeat

The C9orf72 hexanucleotide repeat expansion (HRE) is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It follows autosomal dominant inheritance in families, however, a high proportion of cases are sporadic, raising the possibility of parental premutation. We have demonstrated that intermediate-length alleles (IAs) with >18 repeats (allele frequency ~1%) belong to the same pool of haplotypes as the HRE, suggesting shared ancestry. Here, we tested whether alleles with >18 repeats expand in parental transmission. We used two repeat-primed PCR methods to analyze allele lengths in 539 genetically unselected parent-offspring pairs and in 152 pairs known to carry the SNP (rs139185008*C) that tags >18 repeat IAs and the HRE in Finland. We discovered intergenerational repeat length changes only in >20 repeat alleles. A significant (P = 0.0059) sex bias in 6-40 repeat alleles was noted using a logistic regression model. In this allele range, 12 out of 16 expansions were paternally inherited and 6 out of 7 contractions were maternally inherited. The expansion rate of 20-40 repeat alleles was 34 % in paternal and 11 % in maternal transmissions. In the 20-40 repeat range, most intergenerational expansions were 1-4 repeats in size (15/16), but one larger jump, a paternal expansion from 27 to 73 repeats, was observed. These results demonstrate that alleles with >20 repeats have an increased likelihood of instability, that a paternal expansion bias is observed in alleles with 20-40 repeats, and that expansion events are predominantly 1-4 repeats in size.

genetics↗

bioRxiv2025

Blood donor biobank pipeline to collect genome-based samples for research

The integration of genome data with electronic health records, driven by large biobank studies, has advanced human genetics by allowing systematic exploration of genotype-phenotype links. Regular donation enables large, longitudinal sample cohorts. Because blood donors are generally healthy, disease treatments or progression do not disturb interpretations in functional studies. We describe here a pipeline on how to collect blood donors high quality plasma, serum, and living cell samples for multi-omics studies. Peripheral blood mononuclear cells (PBMC) were frozen and, after thawing, contained standard levels of immune cell subpopulations, responded to immune activation, and were of good quality starting material for multi-omics and cell imaging studies. We demonstrate that most genetic variants of interest to the major genomics study in Finland, FinnGen, could be found by random collection of samples during the standard blood donation without recall. Probing simple associations in the multi-omics data confirmed expected associations with e.g. age and sex, demonstrating good sample quality. As an example of interesting findings, we observed a significant association between frequent blood donation and lower levels of per- and polyfluoroalkyl substances (PFAS). The study demonstrates that regular blood donors are a suitable target population for high-quality, cost-effective sample collections.

molecular biology↗

bioRxiv2024

Morphological single-cell analysis of peripheral blood mononuclear cells from 390 healthy blood donors with Blood Cell Painting

The morphological diversity of blood immune cells of healthy individuals, critical for recognizing disease-related phenotypes, remains largely uncharacterized. To address this gap, we developed Blood Cell Painting (BCP): a high content, high throughput fluorescence imaging assay for peripheral blood mononuclear cells. We generated a BCP Atlas with images of 50 million cells from 390 healthy blood donors, identifying 18 distinct immune cell morphology clusters. A genome-wide association study of BCP-derived imaging-based cellular features revealed 93 significant associations across 30 genetic loci. These loci include genes linked to mast cell function, inflammation, immune signaling, mitochondrial maintenance and circadian immune modulation. We also observed correlations between immune cell morphological features and clinical traits, such as respiratory conditions and healthcare visits related to contraceptive management, potentially reflecting hormonal influences on immune cell phenotypes. As a proof of concept for clinical application, acute myeloid leukemia subtypes were distinguished by BCP. Our study establishes BCP as a versatile method for immune cell profiling to uncover genetic, phenotypic and clinical determinants of immune cell morphology in health and disease.

cell biology↗

bioRxiv2023

SIRPα controls CD47-dependent platelet clearance in mice and humans

Over the last decade, more data has revealed that increased surface expression of the "dont eat me" CD47 protein on cancer cells plays a role in immune evasion and tumor progression, with CD47 blockade emerging as a new therapy in immuno-oncology. CD47 is critical in regulating cell homeostasis and clearance, as binding of CD47 to the inhibitory receptor SIRP can prevent phagocytosis and macrophage-mediated cell clearance. The purpose of this study was to examine the role of the CD47-SIRP signal in platelet homeostasis and clearance. Therapeutic reagents targeting the CD47-SIRP axis are very promising for treatment of hematologic malignancies and solid tumors, but lead to transient anemia or thrombocytopenia in a subset of patients. We found that platelet homeostatic clearance is regulated through the CD47-SIRP axis and that therapeutic blockade to disrupt this interaction in mice and in humans has a significant impact on platelet levels. Furthermore, we identified genetic variations at the SIRPA locus that impact platelet levels in humans such that higher SIRPA gene expression is associated with higher platelet levels. SIRPA expression at either end of the normal range may affect clinical outcomes of treatment with anti-CD47 therapy. Key pointsO_LIPlatelet homeostasis is regulated through the CD47-SIRP axis and therapeutic blockade to disrupt this interaction impacts platelet levels C_LIO_LICommon genetic variants at SIRPA locus associate with platelet levels C_LI

immunology↗

bioRxiv2022

Novel Association of Lyme Disease, Age, and Atopic Dermatitis

Borrelia burgdorferi (B. burgdorferi) is a bacterial spirochete that can cause Lyme disease after infecting a susceptible host. Immune responses to the bacteria are highly variable and host specific. The murine substrain, C3H/HeJ, is a frequently utilized mouse model of Lyme disease. In this study, we sought to investigate the correlation of age with onset and severity of dermatitis, both in mice infected with B. burgdorferi as well as humans who have had a diagnosis of Lyme disease. Female C3H/HeJ mice aged 6-8 weeks, 1 year, or 2 years were infected intraperitoneally with 105 B. burgdorferi. Dermatitis of the tail was evaluated by gross examination and histology. Additional female C3H/HeJ and C57BL/6J mice aged 5 weeks were injected intradermally with 105 B. burgdorferi containing the luciferase reporter gene then analyzed under in vivo imaging. Human data via electronic health records of 342,499 Finnish individuals was tested and analyzed for associations between Lyme disease and atopic dermatitis. Dermatitis worsened over the course of untreated infection, with ulceration, hemorrhaging, flaking, hair loss, and dark lesions as well as spongiosis and acanthosis. These features of dermatitis were present in infected mice after 1 year of age. We further confirm the presence of B. burgdorferi in the tail through quantification of bioluminescence and immunohistochemistry of both C3H/HeJ and C57BL/6J mice. This relationship among Lyme disease, atopic dermatitis, and host age seen in the mouse model is consistent with a large pool (342,499) of human epidemiological data from Finland. We identified 5,248 individuals with Lyme disease and 17,233 with atopic dermatitis in FinnGen. Retrospective analysis shows Lyme disease is associated with atopic dermatitis (OR = 1.91 [1.68 -2.37], P < 2e-16). More visits due to Lyme disease complications (3 or more visits versus 1 visit) were associated with atopic dermatitis (OR = 2.19 [1.35-3.55], P = 0.0014) and risk of developing atopic dermatitis over time (HR=2.26 [1.54-3.95], P = 0.0017). Data from mice and humans reveal a novel relationship among Lyme disease, age, and atopic dermatitis. Through defined pathological scoring, we demonstrate the onset of murine atopic dermatitis with B. burgdorferi infection, which is further exacerbated by host age at time of infection. In humans, a diagnosis of Lyme disease in FinnGen was associated with atopic dermatitis and further research is warranted to establish causation.

immunology↗

bioRxiv2020

An efficient and accurate frailty model approach for genome-wide survival association analysis controlling for population structure and relatedness in large-scale biobanks

With decades of electronic health records linked to genetic data, large biobanks provide unprecedented opportunities for systematically understanding the genetics of the natural history of complex diseases. Genome-wide survival association analysis can identify genetic variants associated with ages of onset, disease progression and lifespan. We developed an efficient and accurate frailty (random effects) model approach for genome-wide survival association analysis of censored time-to-event (TTE) phenotypes in large biobanks by accounting for both population structure and relatedness. Our method utilizes state-of-the-art optimization strategies to reduce the computational cost. The saddlepoint approximation is used to allow for analysis of heavily censored phenotypes (>90%) and low frequency variants (down to minor allele count 20). We demonstrated the performance of our method through extensive simulation studies and analysis of five TTE phenotypes, including lifespan, with heavy censoring rates (90.9% to 99.8%) on ~400,000 UK Biobank participants with white British ancestry and ~180,000 samples in FinnGen, respectively. We further performed genome-wide association analysis for 871 TTE phenotypes in UK Biobank and presented the genome-wide scale phenome-wide association (PheWAS) results with the PheWeb browser.

genomics↗

bioRxiv2019

Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan

Human genetics seeks a way to improve human health on a global scale. Expectations are running high for polygenic risk scores (PRSs) to be translated into clinical practice to predict an inborn susceptibility to health risks. While risk stratification based on PRS is one way to promote population health, a strategy to utilize genetics to prioritize modifiable risk factors and biomarkers driving heath outcome is also warranted. To this end, here we utilized PRSs to comprehensively investigate the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (ntotal = 675,898). First, we conducted genome-wide association studies for 45 quantitative clinical phenotypes, constructed the individual PRSs, and associated them with the age at death of 179,066 participants in BioBank Japan. The PRSs revealed that the genetic susceptibility of high systolic blood pressure (sBP) was strongly associated with a shorter lifespan (hazard ratio [HR] = 1.03, P = 1.4x10-7). Next, we sought to replicate these associations in individuals of European ancestry in UK Biobank (n = 361,194) and FinnGen (n = 135,638). Among the investigated traits, the individuals with higher blood pressure-related PRSs were trans-ethnically associated with a shorter lifespan (HR = 1.03, Pmeta = 3.9x10-13 for sBP) and parental lifespan (HR = 1.06, PUKBB = 2.0x10-86 for sBP). Further, our trans-biobank study identified additional complex traits associated with lifespan (e.g., obesity, height, serum lipids, and platelet counts). Of them, obesity-related traits showed strikingly heterogeneous effects on lifespan between Japanese and European populations (Pheterogeneity = 9.5x10-8 for body mass index). Through trans-ethnic biobank collaboration, we elucidated the novel value of the PRS study in genetics-driven prioritization of risk factors and biomarkers which can be medically intervened to improve population health.

genetics↗

bioRxiv2019

Polygenic Hyperlipidemias and Coronary Artery Disease Risk

BackgroundHyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk.\n\nMethods and ResultsWe derived polygenic risk scores (PRS) with [~]6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with [~]500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project.\n\nIn FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95th percentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS).\n\nConclusionsThe CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.

genomics↗

bioRxiv2019

Polygenic and clinical risk scores and their impact on age at onset of cardiometabolic diseases and common cancers

BackgroundPolygenic risk scores (PRS) have shown promise in predicting susceptibility to common diseases. However, the extent to which PRS and clinical risk factors act jointly and identify high-risk individuals for early onset of disease is unknown.\n\nMethodsWe used large-scale biobank data (the FinnGen study; n=135,300), with up to 46 years of prospective follow-up, and the FINRISK study with standardized clinical risk factor measurements to build genome-wide PRSs with >6M variants for coronary heart disease (CHD), type 2 diabetes (T2D), atrial fibrillation (AF), and breast and prostate cancer. We evaluated their associations with first disease events, age at disease onset, and impact together with routinely used clinical risk scores for predicting future disease.\n\nResultsCompared to the 20-80th percentiles, a PRS in the top 2.5% translated into hazard ratios (HRs) for incident disease ranging from 2.03 to 4.28 (p-values 1.96x10-59 to <1.00x10-100) and the bottom 2.5% into HRs ranging from 0.20 to 0.61. The estimated difference in age at disease onset between top and bottom 2.5% of PRSs was 6 to 13 years. Among early-onset cases, 21.3-32.9% had a PRS in the highest decile and in CHD and AF.\n\nConclusionsThe properties of PRS were similar in all five diseases. PRS identified a considerable proportion early-onset cases, and for all ages the performance of PRS was comparable to established clinical risk scores. These findings warrant further clinical studies on application of polygenic risk information for stratified screening or for guiding lifestyle and preventive medical interventions.

genomics↗

bioRxiv2019

Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data in UK Biobank and FinnGen to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through protein-altering variant association analysis we find a missense variant in UK Biobank (rs28991009 (MAF=0.8%) genotyped in 81,527 individuals with measured IOP and an independent set of 4,269 glaucoma patients and 251,355 controls) that significantly lowers IOP ({beta} = -0.73 mmHg for heterozygotes, -2.96 mmHg for homozygotes, P = 1 x 10-13) and is associated with 34% reduced risk of glaucoma (P = 0.005). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.1%), which was genotyped in 5,177 glaucoma patients and 130,461 controls and is associated with 30% lower glaucoma risk (P = 1 x 10-9). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.002), suggesting the protective mechanism likely resides in the loss of an interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma

genetics↗

bioRxiv2019

Genetics of 38 blood and urine biomarkers in the UK Biobank

Clinical laboratory tests are a critical component of the continuum of care and provide a means for rapid diagnosis and monitoring of chronic disease. In this study, we systematically evaluated the genetic basis of 38 blood and urine laboratory tests measured in 358,072 participants in the UK Biobank and identified 1,857 independent loci associated with at least one laboratory test, including 488 large-effect protein truncating, missense, and copy-number variants. We tested these loci for enrichment in specific single cell types in kidney, liver, and pancreas relevant to disease aetiology. We then causally linked the biomarkers to medically relevant phenotypes through genetic correlation and Mendelian randomization. Finally, we developed polygenic risk scores (PRS) for each biomarker and built multi-PRS models using all 38 PRSs simultaneously. We found substantially improved prediction of incidence in FinnGen (n=135,500) with the multi-PRS relative to single-disease PRSs for renal failure, myocardial infarction, liver fat percentage, and alcoholic cirrhosis. Together, our results show the genetic basis of these biomarkers, which tissues contribute to the biomarker function, the causal influences of the biomarkers, and how we can use this to predict disease.

genetics↗

bioRxiv2019

Polygenic risk score of alcohol consumption predicts alcohol-related morbidity and all-cause mortality

ObjectiveTo develop a highly polygenic risk score (PRS) for alcohol consumption and study whether it predicts alcohol-related morbidity and all-cause mortality.\n\nDesignBiobank-based prospective cohort study\n\nSettingFinnGen Study (Finland)\n\nParticipants96,499 genotyped participants from the nationwide prospective FinnGen study and 36,499 participants from prospective cohorts (Health 2000, FINRISK, Twin Cohort) with detailed baseline data and up to 25 years of follow-up time.\n\nMain outcome measuresIncident alcohol-related morbidity and alcohol-related or all-cause mortality, based on hospitalizations, outpatient specialist care, drug purchases, and death reports.\n\nResultsIn 96,499 FinnGen participants there were in total 4,785 first-observed incident alcohol-related health events. The PRS of alcohol consumption was associated with alcohol-related morbidity and the risk estimate (hazard ratio, HR) between the highest and lowest quintiles of the PRS was 1.67 [ 95 % confidence interval: 1.52-1.84], p=3.2*10-27). In 28,639 participants with comprehensive baseline data from prospective Health 2000 and FINRISK cohorts, 911 incident first alcohol-related events were observed. When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI=[1.26-1.99], p=8.2*10-5). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI=[1.2-1.47], p=4.5e-08) in the adjusted model. In all 39,695 participants with self-reported alcohol consumption available, a 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption ({beta}=11.2 [9.85-12.58 g], p = 2.3*10-58).\n\nConclusionsThe PRS for alcohol consumption associates for both alcohol-related morbidity and all-cause mortality. These findings underline the importance of heritable factors in alcohol-related behavior and the related health burden. The results highlight how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.

genomics↗