Gout is the most common inflammatory joint disease caused by the crystallization of urate inside the joints. Patients with gout typically have abnormal blood lipid and sugar levels, which are associated with cardiovascular diseases. However, the relationship between gout and metabolic changes is unclear. Our goal was two-fold: to identify new gout risk factors using genome-wide association analysis and subsequently to investigate the effects of the identified risk alleles on metabolic measures in the bloodstream. We performed a genome-wide meta-analysis for gout in the FinnGen project, the Estonian Biobank, and the UK Biobank, encompassing a total of 992,583 individuals, including 17,972 gout cases. Given that gout is commonly recognized as a disease affecting the elderly, and males specifically, we further explored age- and sex-stratified genetic associations in FinnGen (10,885 cases and 366,392 controls). Finally, we determined the metabolomic consequences of the gout risk-increasing alleles using data from a large metabolomics GWAS. In the meta-analysis, we observed 32 genome-wide significant (P<5x10⁻⁸) loci, one of which was novel. In the age- and sex-stratified analyses, we additionally identified one novel gout-associated locus in the male subgroup. The metabolomic findings suggested that the majority of the gout risk alleles primarily affected urate concentration in the bloodstream but not the concentrations of lipids and other metabolites. Therefore, it appears that the associations between gout and metabolic factors at the population level are likely explained by shared lifestyle risk factors. In conclusion, our study sheds new light on the genetic architecture of gout and adds to the growing body of evidence supporting the role of urate, but not other metabolic measures, including lipoprotein lipids and glucose, as a key risk factor for developing gout.

The authors have declared no competing interest.

E.S. was funded by Academy of Finland (grant number: 338229) and Orion Research Foundation sr. J.K. was funded by Sigrid Juselius foundation. The authors wish to acknowledge CSC - IT Center for Science, Finland, for computational resources. We also want to acknowledge the participants and investigators of FinnGen study. 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 Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sarl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis Pharma AG, and Boehringer Ingelheim International GmbH. Following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (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 (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta), Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/) and Arctic Biobank (https://www.oulu.fi/en/university/faculties-and-units/faculty-medicine/northern-finland-birth-cohorts-and-arctic-biobank). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). 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.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Patients and control subjects in FinnGen provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, separate research cohorts, collected prior the Finnish Biobank Act came into effect (in September 2013) and start of FinnGen (August 2017), were collected based on study-specific consents and later transferred to the Finnish biobanks after approval by Fimea (Finnish Medicines Agency), the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Fimea. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) statement number for the FinnGen study is Nr HUS/990/2017. The FinnGen study is approved by Finnish Institute for Health and Welfare (permit numbers: THL/2031/6.02.00/2017, THL/1101/5.05.00/2017, THL/341/6.02.00/2018, THL/2222/6.02.00/2018, THL/283/6.02.00/2019, THL/1721/5.05.00/2019 and THL/1524/5.05.00/2020), Digital and population data service agency (permit numbers: VRK43431/2017-3, VRK/6909/2018-3, VRK/4415/2019-3), the Social Insurance Institution (permit numbers: KELA 58/522/2017, KELA 131/522/2018, KELA 70/522/2019, KELA 98/522/2019, KELA 134/522/2019, KELA 138/522/2019, KELA 2/522/2020, KELA 16/522/2020), Findata permit numbers THL/2364/14.02/2020, THL/4055/14.06.00/2020,THL/3433/14.06.00/2020, THL/4432/14.06/2020, THL/5189/14.06/2020, THL/5894/14.06.00/2020, THL/6619/14.06.00/2020, THL/209/14.06.00/2021, THL/688/14.06.00/2021, THL/1284/14.06.00/2021, THL/1965/14.06.00/2021, THL/5546/14.02.00/2020, THL/2658/14.06.00/2021, THL/4235/14.06.00/202, Statistics Finland (permit numbers: TK-53-1041-17 and TK/143/07.03.00/2020 (earlier TK-53-90-20) TK/1735/07.03.00/2021, TK/3112/07.03.00/2021) and Finnish Registry for Kidney Diseases permission/extract from the meeting minutes on 4th July 2019.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The individual-level data are available under restricted access for legal and ethical reasons. Formal approval for the researchers is required to access the data: please see https://www.finngen.fi/en/access_results for more details. Access to individual-level data and genotype data is managed by the Finnish Biobank Cooperative at the Fingenious portal [https://site.fingenious.fi/en/]). The metabolomics GWAS summary statistics used in this study have been made publicly available through the NHGRI-EBI GWAS catalogue (GCST90301941-GCST90302173) and https://www.phpc.cam.ac.uk/ceu/lipids-and-metabolites/ . Summary statistics of this study will be made available through the NHGRI-EBI GWAS catalogue upon publication.