Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
Justice AE., Karaderi T., Highland HM., Young KL., Graff M., Lu Y., Turcot V., Auer PL., Fine RS., Guo X., Schurmann C., Lempradl A., Marouli E., Mahajan A., Winkler TW., Locke AE., Medina-Gomez C., Esko T., Vedantam S., Giri A., Lo KS., Alfred T., Mudgal P., Ng MCY., Heard-Costa NL., Feitosa MF., Manning AK., Willems SM., Sivapalaratnam S., Abecasis G., Alam DS., Allison M., Amouyel P., Arzumanyan Z., Balkau B., Bastarache L., Bergmann S., Bielak LF., Blüher M., Boehnke M., Boeing H., Boerwinkle E., Böger CA., Bork-Jensen J., Bottinger EP., Bowden DW., Brandslund I., Broer L., Burt AA., Butterworth AS., Caulfield MJ., Cesana G., Chambers JC., Chasman DI., Chen Y-DI., Chowdhury R., Christensen C., Chu AY., Collins FS., Cook JP., Cox AJ., Crosslin DS., Danesh J., de Bakker PIW., Denus SD., Mutsert RD., Dedoussis G., Demerath EW., Dennis JG., Denny JC., Di Angelantonio E., Dörr M., Drenos F., Dubé M-P., Dunning AM., Easton DF., Elliott P., Evangelou E., Farmaki A-E., Feng S., Ferrannini E., Ferrieres J., Florez JC., Fornage M., Fox CS., Franks PW., Friedrich N., Gan W., Gandin I., Gasparini P., Giedraitis V., Girotto G., Gorski M., Grallert H., Grarup N., Grove ML., Gustafsson S., Haessler J., Hansen T., Hattersley AT., Hayward C., Heid IM., Holmen OL., Hovingh GK., Howson JMM., Hu Y., Hung Y-J., Hveem K., Ikram MA., Ingelsson E., Jackson AU., Jarvik GP., Jia Y., Jørgensen T., Jousilahti P., Justesen JM., Kahali B., Karaleftheri M., Kardia SLR., Karpe F., Kee F., Kitajima H., Komulainen P., Kooner JS., Kovacs P., Krämer BK., Kuulasmaa K., Kuusisto J., Laakso M., Lakka TA., Lamparter D., Lange LA., Langenberg C., Larson EB., Lee NR., Lee W-J., Lehtimäki T., Lewis CE., Li H., Li J., Li-Gao R., Lin L-A., Lin X., Lind L., Lindström J., Linneberg A., Liu C-T., Liu DJ., Luan J., Lyytikäinen L-P., MacGregor S., Mägi R., Männistö S., Marenne G., Marten J., Masca NGD., McCarthy MI., Meidtner K., Mihailov E., Moilanen L., Moitry M., Mook-Kanamori DO., Morgan A., Morris AP., Müller-Nurasyid M., Munroe PB., Narisu N., Nelson CP., Neville M., Ntalla I., O'Connell JR., Owen KR., Pedersen O., Peloso GM., Pennell CE., Perola M., Perry JA., Perry JRB., Pers TH., Ewing A., Polasek O., Raitakari OT., Rasheed A., Raulerson CK., Rauramaa R., Reilly DF., Reiner AP., Ridker PM., Rivas MA., Robertson NR., Robino A., Rudan I., Ruth KS., Saleheen D., Salomaa V., Samani NJ., Schreiner PJ., Schulze MB., Scott RA., Segura-Lepe M., Sim X., Slater AJ., Small KS., Smith BH., Smith JA., Southam L., Spector TD., Speliotes EK., Stefansson K., Steinthorsdottir V., Stirrups KE., Strauch K., Stringham HM., Stumvoll M., Sun L., Surendran P., Swart KMA., Tardif J-C., Taylor KD., Teumer A., Thompson DJ., Thorleifsson G., Thorsteinsdottir U., Thuesen BH., Tönjes A., Torres M., Tsafantakis E., Tuomilehto J., Uitterlinden AG., Uusitupa M., van Duijn CM., Vanhala M., Varma R., Vermeulen SH., Vestergaard H., Vitart V., Vogt TF., Vuckovic D., Wagenknecht LE., Walker M., Wallentin L., Wang F., Wang CA., Wang S., Wareham NJ., Warren HR., Waterworth DM., Wessel J., White HD., Willer CJ., Wilson JG., Wood AR., Wu Y., Yaghootkar H., Yao J., Yerges-Armstrong LM., Young R., Zeggini E., Zhan X., Zhang W., Zhao JH., Zhao W., Zheng H., Zhou W., Zillikens MC., Rivadeneira F., Borecki IB., Pospisilik JA., Deloukas P., Frayling TM., Lettre G., Mohlke KL., Rotter JI., Kutalik Z., Hirschhorn JN., Cupples LA., Loos RJF., North KE., Lindgren CM., CHD Exome+ Consortium None., Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium None., EPIC-CVD Consortium None., ExomeBP Consortium None., Global Lipids Genetic Consortium None., GoT2D Genes Consortium None., InterAct None., ReproGen Consortium None., T2D-Genes Consortium None., MAGIC Investigators None.
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.