A Principal Component Meta-analysis on Multiple Anthropometric Traits Identifies Novel Loci for Body Shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

Citing Articles

Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study.

Morales-Berstein F, Khouja J, Gormley M, Ebrahimi E, Virani S, McKay J medRxiv. 2025; .

PMID: 39974030 PMC: 11838947. DOI: 10.1101/2024.11.21.24317707.

Genome-wide association analysis of composite sleep health scores in 413,904 individuals.

Goodman M, Faquih T, Paz V, Nagarajan P, Lane J, Spitzer B Commun Biol. 2025; 8(1):115.

PMID: 39856408 PMC: 11760956. DOI: 10.1038/s42003-025-07514-0.

Nature or nurture: genetic and environmental predictors of adiposity gain in adults.

Peruchet-Noray L, Dimou N, Cordova R, Fontvieille E, Jansana A, Gan Q EBioMedicine. 2024; 111():105510.

PMID: 39689375 PMC: 11720109. DOI: 10.1016/j.ebiom.2024.105510.

Association of body shape phenotypes and body fat distribution indexes with inflammatory biomarkers in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank.

Gonzalez-Gil E, Peruchet-Noray L, Sedlmeier A, Christakoudi S, Biessy C, Navionis A BMC Med. 2024; 22(1):334.

PMID: 39148045 PMC: 11328449. DOI: 10.1186/s12916-024-03544-3.

Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer.

Peruchet-Noray L, Sedlmeier A, Dimou N, Baurecht H, Fervers B, Fontvieille E Sci Adv. 2024; 10(16):eadj1987.

PMID: 38640244 PMC: 11029802. DOI: 10.1126/sciadv.adj1987.

References

Willer C, Schmidt E, Sengupta S, Peloso G, Gustafsson S, Kanoni S . Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013; 45(11):1274-1283. PMC: 3838666. DOI: 10.1038/ng.2797. View

Paternoster L, Evans D, Nohr E, Holst C, Gaborieau V, Brennan P . Genome-wide population-based association study of extremely overweight young adults--the GOYA study. PLoS One. 2011; 6(9):e24303. PMC: 3174168. DOI: 10.1371/journal.pone.0024303. View

Grundberg E, Small K, Hedman A, Nica A, Buil A, Keildson S . Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet. 2012; 44(10):1084-9. PMC: 3784328. DOI: 10.1038/ng.2394. View

Denny J, Ritchie M, Basford M, Pulley J, Bastarache L, Brown-Gentry K . PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics. 2010; 26(9):1205-10. PMC: 2859132. DOI: 10.1093/bioinformatics/btq126. View

Myint P, Kwok C, Luben R, Wareham N, Khaw K . Body fat percentage, body mass index and waist-to-hip ratio as predictors of mortality and cardiovascular disease. Heart. 2014; 100(20):1613-9. DOI: 10.1136/heartjnl-2014-305816. View

Aulchenko Y, Ripke S, Isaacs A, Van Duijn C . GenABEL: an R library for genome-wide association analysis. Bioinformatics. 2007; 23(10):1294-6. DOI: 10.1093/bioinformatics/btm108. View

Li M, Wang P, Liu X, Lim E, Wang Z, Yeager M . GWASdb: a database for human genetic variants identified by genome-wide association studies. Nucleic Acids Res. 2011; 40(Database issue):D1047-54. PMC: 3245026. DOI: 10.1093/nar/gkr1182. View

Polderman T, Benyamin B, de Leeuw C, Sullivan P, van Bochoven A, Visscher P . Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet. 2015; 47(7):702-9. DOI: 10.1038/ng.3285. View

Ramdas M, Harel C, Armoni M, Karnieli E . AHNAK KO mice are protected from diet-induced obesity but are glucose intolerant. Horm Metab Res. 2014; 47(4):265-72. DOI: 10.1055/s-0034-1387736. View

10.

Meyre D, Delplanque J, Chevre J, Lecoeur C, Lobbens S, Gallina S . Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet. 2009; 41(2):157-9. DOI: 10.1038/ng.301. View

11.

Soto-Pantoja D, Kaur S, Roberts D . CD47 signaling pathways controlling cellular differentiation and responses to stress. Crit Rev Biochem Mol Biol. 2015; 50(3):212-30. PMC: 4822708. DOI: 10.3109/10409238.2015.1014024. View

12.

Kilpelainen T, Zillikens M, Stancakova A, Finucane F, Ried J, Langenberg C . Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nat Genet. 2011; 43(8):753-60. PMC: 3262230. DOI: 10.1038/ng.866. View

13.

He M, Xu M, Zhang B, Liang J, Chen P, Lee J . Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci. Hum Mol Genet. 2014; 24(6):1791-800. PMC: 4351379. DOI: 10.1093/hmg/ddu583. View

14.

Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H . The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2013; 42(Database issue):D1001-6. PMC: 3965119. DOI: 10.1093/nar/gkt1229. View

15.

Beck T, Hastings R, Gollapudi S, Free R, Brookes A . GWAS Central: a comprehensive resource for the comparison and interrogation of genome-wide association studies. Eur J Hum Genet. 2013; 22(7):949-52. PMC: 4060122. DOI: 10.1038/ejhg.2013.274. View

16.

Lango Allen H, Estrada K, Lettre G, Berndt S, Weedon M, Rivadeneira F . Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010; 467(7317):832-8. PMC: 2955183. DOI: 10.1038/nature09410. View

17.

Wang H, Hou Q, Guo Q, Li T, Wu D, Zhang X . DNA methylation study of fetus genome through a genome-wide analysis. BMC Med Genomics. 2014; 7:18. PMC: 3996908. DOI: 10.1186/1755-8794-7-18. View

18.

Teslovich T, Musunuru K, Smith A, Edmondson A, Stylianou I, Koseki M . Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010; 466(7307):707-13. PMC: 3039276. DOI: 10.1038/nature09270. View

19.

Wheeler E, Huang N, Bochukova E, Keogh J, Lindsay S, Garg S . Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet. 2013; 45(5):513-7. PMC: 4106235. DOI: 10.1038/ng.2607. View

20.

Wood A, Esko T, Yang J, Vedantam S, Pers T, Gustafsson S . Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014; 46(11):1173-86. PMC: 4250049. DOI: 10.1038/ng.3097. View