Is There Causal Relationship of Smoking and Alcohol Consumption with Bone Mineral Density? A Mendelian Randomization Study
Observational studies examining associations of smoking and alcohol consumption with bone mineral density (BMD) have generated inconsistent results and suffer from several methodological limitations. We aim to evaluate whether there are causal associations between smoking, alcohol consumption, and BMD using a Mendelian randomization (MR) design. Genetic variants associated with smoking status (n = 142), no. of cigarettes smoked per day (CPD) (n = 3), smoking initiation (n = 1), and alcohol consumption (n = 6) identified in published genome-wide association studies (GWAS) were used as instruments. Summary statistics data of 32735, 28498, 8143, and 445921 European subjects included in The GEnetic Factors for Osteoporosis Consortium or UK Biobank were used to generate associations of genetically predicted smoking or alcohol consumption with femoral neck (FN-BMD), lumbar spine (LS-BMD), forearm (FA-BMD), and heel BMD, respectively, by using the inverse-variance weighted method. The BMD was measured using either ultrasound (for heel) or Dual-energy X-ray Absorptiometry (for others). In our analyses, smoking status tended to be negatively associated with several types of BMD (heel BMD: β = − 0.053, p = 0.003; FN-BMD: β = − 0.139, p = 0.053; FA-BMD: β = − 0.264, p = 0.077), although the association with LS-BMD was null. Smoking initiation was significantly inversely associated with heel BMD (β = − 0.201, p = 3.60 × 10−8). CPD was associated with a lower FN-BMD (β = − 0.014, p = 0.047) only. There was no clear association of genetically predicted alcohol consumption with BMD. Our study provided some evidence of a potential association between genetically predicted smoking and lower BMD, especially for heel BMD, but not for alcohol consumption. Considering the inconsistent findings with the different types of BMD and limitations of the current work, further studies are needed to better characterize the exact relationship between smoking, alcohol consumption, and BMD.
KeywordsBone mineral density Smoking Alcohol consumption Association Mendelian randomization Genetic instruments
RG, LW, and QF designed this study. RG and QF performed the catalog and literature search and data extraction with suggestions and help from LW. RG, LW, and QF performed the statistical analyses. All authors contributed to the data interpretation and manuscript writing. QF is responsible for the overall content as the guarantor of the paper.
This study was supported by the General project for scientific research of Liaoning Provincial Education Department (No. L2015572 for Ran Guo). The sponsors are not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Compliance with Ethical Standards
Conflict of interest
Ran Guo, Lang Wu, and Qin Fu declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
- 10.Kutalik Z, Benyamin B, Bergmann S, Mooser V, Waeber G, Montgomery GW, Martin NG, Madden PA, Heath AC, Beckmann JS, Vollenweider P, Marques-Vidal P, Whitfield JB (2011) Genome-wide association study identifies two loci strongly affecting transferrin glycosylation. Hum Mol Genet 20:3710–3717CrossRefPubMedCentralGoogle Scholar
- 11.Kapoor M, Wang JC, Wetherill L, Le N, Bertelsen S, Hinrichs AL, Budde J, Agrawal A, Bucholz K, Dick D, Harari O, Hesselbrock V, Kramer J, Nurnberger JI Jr, Rice J, Saccone N, Schuckit M, Tischfield J, Porjesz B, Edenberg HJ, Bierut L, Foroud T, Goate A (2013) A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks. Hum Genet 132:1141–1151CrossRefPubMedCentralGoogle Scholar
- 12.Schumann G, Coin LJ, Lourdusamy A, Charoen P, Berger KH, Stacey D, Desrivieres S, Aliev FA, Khan AA, Amin N, Aulchenko YS, Bakalkin G, Bakker SJ, Balkau B, Beulens JW, Bilbao A, de Boer RA, Beury D, Bots ML, Breetvelt EJ, Cauchi S, Cavalcanti-Proenca C, Chambers JC, Clarke TK, Dahmen N, de Geus EJ, Dick D, Ducci F, Easton A, Edenberg HJ, Esko T, Fernandez-Medarde A, Foroud T, Freimer NB, Girault JA, Grobbee DE, Guarrera S, Gudbjartsson DF, Hartikainen AL, Heath AC, Hesselbrock V, Hofman A, Hottenga JJ, Isohanni MK, Kaprio J, Khaw KT, Kuehnel B, Laitinen J, Lobbens S, Luan J, Mangino M, Maroteaux M, Matullo G, McCarthy MI, Mueller C, Navis G, Numans ME, Nunez A, Nyholt DR, Onland-Moret CN, Oostra BA, O’Reilly PF, Palkovits M, Penninx BW, Polidoro S, Pouta A, Prokopenko I, Ricceri F, Santos E, Smit JH, Soranzo N, Song K, Sovio U, Stumvoll M, Surakk I, Thorgeirsson TE, Thorsteinsdottir U, Troakes C, Tyrfingsson T, Tonjes A, Uiterwaal CS, Uitterlinden AG, van der Harst P, van der Schouw YT, Staehlin O, Vogelzangs N, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Whitfield JB, Wichmann EH, Willemsen G, Witteman JC, Yuan X, Zhai G, Zhao JH, Zhang W, Martin NG, Metspalu A et al (2011) Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci USA 108:7119–7124CrossRefPubMedCentralGoogle Scholar
- 13.Loh P-R, Kichaev G, Gazal S, Schoech AP, Price AL. Mixed model association for biobank-scale data sets. BioRXiv. https://doi.org/10.1101/194944 (2018)
- 16.Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, Dahia CL, Park-Min KH, Tobias JH, Kooperberg C, Kleinman A, Styrkarsdottir U, Liu CT, Uggla C, Evans DS, Nielson CM, Walter K, Pettersson-Kymmer U, McCarthy S, Eriksson J, Kwan T, Jhamai M, Trajanoska K, Memari Y, Min J, Huang J, Danecek P, Wilmot B, Li R, Chou WC, Mokry LE, Moayyeri A, Claussnitzer M, Cheng CH, Cheung W, Medina-Gomez C, Ge B, Chen SH, Choi K, Oei L, Fraser J, Kraaij R, Hibbs MA, Gregson CL, Paquette D, Hofman A, Wibom C, Tranah GJ, Marshall M, Gardiner BB, Cremin K, Auer P, Hsu L, Ring S, Tung JY, Thorleifsson G, Enneman AW, van Schoor NM, de Groot LC, van der Velde N, Melin B, Kemp JP, Christiansen C, Sayers A, Zhou Y, Calderari S, van Rooij J, Carlson C, Peters U, Berlivet S, Dostie J, Uitterlinden AG, Williams SR, Farber C, Grinberg D, LaCroix AZ, Haessler J, Chasman DI, Giulianini F, Rose LM, Ridker PM, Eisman JA, Nguyen TV, Center JR, Nogues X, Garcia-Giralt N, Launer LL, Gudnason V, Mellstrom D, Vandenput L, Amin N, van Duijn CM, Karlsson MK, Ljunggren O, Svensson O, Hallmans G, Rousseau F, Giroux S, Bussiere J, Arp PP et al (2015) Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526:112–117CrossRefPubMedCentralGoogle Scholar
- 20.Clarke TK, Adams MJ, Davies G, Howard DM, Hall LS, Padmanabhan S, Murray AD, Smith BH, Campbell A, Hayward C, Porteous DJ, Deary IJ, McIntosh AM (2017) Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N = 112 117). Mol Psychiatry 22:1376–1384CrossRefPubMedCentralGoogle Scholar
- 34.Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosen T, Lindstedt G, Lundberg PA, Wilske J, Bengtsson BA (1995) Serum intact parathyroid hormone in a random population sample of men and women: relationship to anthropometry, life-style factors, blood pressure, and vitamin D. Calcif Tissue Int 56:104–108CrossRefPubMedCentralGoogle Scholar
- 36.Matsuo K, Hirohata T, Sugioka Y, Ikeda M, Fukuda A (1988) Influence of alcohol intake, cigarette smoking, and occupational status on idiopathic osteonecrosis of the femoral head. Clin Orthop Relat Res 234:115–123Google Scholar