| Title: |
Large-scale genome-wide analyses with proteomics integration reveal novel loci and biological insights into frailty |
| Authors: |
Mak, Jonathan K. L.; Qin, Chenxi; Krüger, Moritz; Kuukka, Anna; FinnGen; Hägg, Sara; Lin, Jake; Jylhävä, Juulia; Mäkitie, Antti; Palotie, Aarno; Daly, Mark; Mäkelä, Tomi P.; Kaprio, Jaakko; Partanen, Jukka; Pitkäranta, Anne; Raivio, Taneli; Ripatti, Samuli; Arvas, Mikko; Carpen, Olli; Raivio, Minna; Tienari, Pentti; Partanen, Juulia; Färkkilä, Martti; Koskela, Jukka; Pikkarainen, Sampsa; Eklund, Kari; Mars, Nina; Kauppi, Paula; Gordin, Daniel; Sinisalo, Juha; Taskinen, Marja-Riitta; Tuomi, Tiinamaija; Hiltunen, Timo; Elliott, Amanda; Reeve, Mary Patricia; Ruotsalainen, Sanni; Joensuu, Heikki; Mattson, Johanna; Salminen, Eveliina; Pitkänen, Esa; Turunen, Joni A.; Ollila, Terhi; Karjalainen, Juha; Hannula-Jouppi, Katariina; Pussinen, Pirkko; Salminen, Aino; Salo, Tuula; Rice, David; Nieminen, Pekka; Palotie, Ulla; Laivuori, Hannele; Heikinheimo, Oskari; Kalliala, Ilkka; Aaltonen, Lauri; Widen, Elisabeth; Tukiainen, Taru; Välimäki, Niko; Hovatta, Iiris; Isometsä, Erkki; Ollila, Hanna; Toppila-Salmi, Sanna; Aarnisalo, Antti; Aittomäki, Kristiina; Åberg, Fredrik; Kurki, Mitja; Havulinna, Aki; Mehtonen, Juha; Palta, Priit; Hassan, Shabbeer; Della Briotta Parolo, Pietro; Lemmelä, Susanna; Liu, Aoxing; Lehisto, Arto Aleksanteri; Ganna, Andrea; Llorens, Vincent; Heyne, Henrike; Rämö, Joel; Rodosthenous, Rodosthenis; Strausz, Satu; Palotie, Tuula; Palin, Kimmo; Kiiskinen, Tuomo; Lee, Jiwoo; Tsuo, Kristin; Hyvärinen, Kati; Ritari, Jarmo; Punkka, Eero; Jalanko, Anu; Shen, Huei-Yi; Kajanne, Risto; Aavikko, Mervi; Cooper, Helen; Öller, Denise; Leinonen, Rasko; Linna, Malla-Maria; Lahtela, L. Elisa; Kaunisto, Mari; Kilpeläinen, Elina; Sipilä, Timo P.; Dada, Oluwaseun Alexander; Ghazal, Awaisa; Kytölä, Anastasia; Weldatsadik, Rigbe; Donner, Kati; Loukola, Anu; Luo, Shuang; Padmanabhuni, Shanmukha Sampath; Tammerluoto, Jyrki |
| Contributors: |
HUS Head and Neck Center; Clinicum; Korva-, nenä- ja kurkkutautien klinikka; HUS Group; Research Programs Unit; Aarno Palotie / Principal Investigator; Institute for Molecular Medicine Finland; Genomics of Neurological and Neuropsychiatric Disorders; Department of Biochemistry and Developmental Biology; Mäkelä Lab; Helsinki Institute of Life Science HiLIFE; Finnish Red Cross Blood Service; Department of Public Health; Samuli Olli Ripatti / Principal Investigator; Complex Disease Genetics; Research Program in Systems Oncology; HUS Radiology and Pathology; Precision Cancer Pathology; Olli Mikael Carpen / Principal Investigator; HUS Neurocenter; Department of Neurosciences; HUS Abdominal Center; Department of Medicine; HUS Inflammation Center; HUS Heart and Lung Center; Marja-Riitta Taskinen Research Group; Tiinamaija Tuomi Research Group; HUS Internal Medicine and Rehabilitation; Department of Oncology; Heikki Joensuu / Principal Investigator; HUS Comprehensive Cancer Center; Department of Medical and Clinical Genetics; HUS Physiology, Genetics and Preanalytics; HUSLAB; Machine learning in biomedicine; Silmäklinikka; Department of Dermatology, Allergology and Venereology; Department of Oral and Maxillofacial Diseases; David Paul Cracroft Rice / Principal Investigator; HUS Gynecology and Obstetrics; Department of Obstetrics and Gynecology; Lauri Antti Aaltonen / Principal Investigator; HUS Diagnostic Center; Elisabeth Ingrid Maria Widen / Principal Investigator; Genomic Discoveries and Clinical Translation; Genomics of Sex Differences; Department of Molecular and Integrative Biosciences; Department of Computer Science; ATG - Applied Tumor Genomics; Mind and Matter; Department of Psychology; Iiris Hovatta / Principal Investigator; Department of Psychiatry; HUS Psychiatry; Kristiina Aittomäki / Principal Investigator; IV kirurgian klinikka; Data Science Genetic Epidemiology Lab; Medicum; Bio Bank; Molecular Systems Biology |
| Publisher Information: |
Springer |
| Publication Year: |
2026 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Uk; Identification; Resource; Health; Index; Biomedicine |
| Description: |
Frailty is a clinically relevant phenotype with notable gaps in our understanding of its etiology. Using the Hospital Frailty Risk Score (HFRS) to define frailty, we performed a genome-wide association study in FinnGen (N = 500,737), replicated the results in the UK Biobank (N = 407,463) and performed a meta-analysis. We prioritized genes through colocalization with expression, splicing and protein quantitative trait loci and proteomics integration. We identified 53 independent lead variants associated with frailty (P < 5 x 10(-8)), of which 45 were novel and not previously reported in the GWAS Catalog. Replication at the individual variant and polygenic risk score of the HFRS (P = 1.86 x 10(-522)) levels and meta-analysis largely confirmed the findings. Colocalization analysis supported a causal role for several genes, including CHST9, C6orf106 (ILRUN), KHK, MET, APOE, CGREF1 and PPP6C. Additionally, plasma levels of MET, CGREF1 and APOE were associated with HFRS. Our results reveal new genetic contributions to frailty and shed light on its biological basis. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
This work was supported by the Swedish Research Council (grant nos. 2018-02077 to J.J., 2019-01272, 2020-06101, 2022-01608), the Research Council of Finland to J.J. (grant no. 3493358), the Sigrid Juselius Foundation to J.J., the Yrjo Jahnsson Foundation to J.J. (grant no. 20217416), Instrumentarium Science Foundation to J.J. and Signe and Ane Gyllenberg Foundation to J.J. (grant no. 6226). This research was conducted using the UK Biobank resource, as part of the registered project 22224. The analyses of UK Biobank genotypes were enabled by resources in project sens2017519 provided by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) at UPPMAX, funded by the Swedish Research Council through grant agreement no. 2022-06725. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie, AstraZeneca, Biogen, Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sarl), Genentech, Merck Sharp & Dohme, Pfizer, GlaxoSmithKline Intellectual Property Development, Sanofi US Services, Maze Therapeutics, Janssen Biotech and Novartis. The following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (https://www.auria.fi/biopankki/), THL Biobank (https://www.thl.fi/biobank/), Helsinki Biobank (https://www.helsinginbiopankki.fi/), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx/), Finnish Clinical Biobank Tampere (https://www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere/), Biobank of Eastern Finland (https://www.ita-suomenbiopankki.fi/en/), Central Finland Biobank (https://www.ksshp.fi/fi-FI/Potilaalle/Biopankki/), Finnish Red Cross Blood Service Biobank (https://www.veripalvelu.fi/verenluovutus/biopankkitoiminta/) and Terveystalo Biobank (https://www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/). All Finnish Biobanks are members of BBMRI.fi infrastructure (https://www.bbmri.fi/). The Finnish Biobank Cooperative-FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.; https://hdl.handle.net/10138/627199; 105015863188; 001544913100001 |
| Availability: |
https://hdl.handle.net/10138/627199 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.F27A4CB3 |
| Database: |
BASE |