Genome wide association study based on clustering by obesity-related variables shed light on a genetic architecture of obesity in Japanese and UK population

Background Many loci associated with obesity have been reported in previous genome-wide association studies (GWASs). However, it remains unclear whether variants at all these loci contributed to onset of obesity or whether one or a few variants cause obesity when obesity is a genetically heterogeneous population. Objective To investigate the genetic architecture of obesity by clustering a population with obesity into clusters using obesity-related factors. Methods This study was based on the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study and the Community-Based Cohort Study. As the Step-1, a GWAS with body mass index (BMI) as an outcome was performed for all 48,365 eligible participants. As the Step-2, we then assigned the 13,067/48,365 participants with obesity (BMI ≥ 25 kg/m2) using the k-prototype to 5 clusters. Obesity-related factors (such as age, nutrient intake, physical activity, sleep duration, difference between weight at age 20 and current weight, smoking, alcohol drinking, psychological distress, and birth weight) were used for clustering. Subsequently, participants in each cluster and those with a BMI < 25 kg/m2 were combined, and GWASs were performed according to the 5 clusters. Additionally, a sub-analysis using data from the UK Biobank was conducted to compare the results. Results The Step-1 detected 18 genes, most of which were reportedly associated with obesity or obesity-related topics in previous studies. The result of Step-2, of the 18 genes detected in Step-1, LINC01741, CRYZL2P-SEC16B , and SEC16B were significantly related to Cluster 2, FTO, PMAIP1 , and MC4R to Cluster 3, and BDNF, BDNF-AS, LINC00678 , and KIF18A to Clusters 4 and 5. In the sub-analysis, a similar phenomenon was observed in which separate obesity-related genes were detected for each cluster. Conclusions Our data support the notion that a decreased sample size with increased homogeneity may reveal insights into the genetic architecture of obesity. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study and the Community-Based Cohort Study were supported by the Japan Agency for Medical Research and Development (AMED) (grant numbers JP20km0105001 and JP21km0105002). This study was also supported by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) KAKENHI (grant numbers 19H03894 and 22H03346). AMED and MEXT had no role in the design or execution of the study. ### Author Declarations 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: The protocol was reviewed and approved by the Institutional Review Board of the Tohoku Medical Megabank Organization[Approval number: 2022-4-089 ]. 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 For the TMM biobank, data are available from the authors upon reasonable request and with the permission of the TMM biobank. All inquiries about access to the data should be sent to the TMM biobank (dist{at}megabank.tohoku.ac.jp). For the UKB, the data will be available to the public by requesting it from UK Biobank. * AS : antisense RNA BDNF : brain-derived neurotrophic factor BirThree Cohort Study : Birth and Three-Generation Cohort Study, CommCohort Study BMI : body mass index cGWAS : cluster-based GWAS FFQ : food frequency questionnaire GRM : genetic relationship matrix GWAS : genome-wide association study HWE : Hardy-Weinberg equilibrium KNN : k-nearest neighbors MAF : minor allele frequency MC4R : melanocortin-4-receptors PCA : principal component analysis SD : standard deviation TMM : Tohoku Medical Megabank Project, Community-Based Cohort Study