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Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

ABSTRACT: Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2?million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

SUBMITTER: Liu M

PROVIDER: S-EPMC6358542 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Liu Mengzhen M Jiang Yu Y Wedow Robbee R Li Yue Y Brazel David M DM Chen Fang F Datta Gargi G Davila-Velderrain Jose J McGuire Daniel D Tian Chao C Zhan Xiaowei X Choquet Hélène H Docherty Anna R AR Faul Jessica D JD Foerster Johanna R JR Fritsche Lars G LG Gabrielsen Maiken Elvestad ME Gordon Scott D SD Haessler Jeffrey J Hottenga Jouke-Jan JJ Huang Hongyan H Jang Seon-Kyeong SK Jansen Philip R PR Ling Yueh Y Mägi Reedik R Matoba Nana N McMahon George G Mulas Antonella A Orrù Valeria V Palviainen Teemu T Pandit Anita A Reginsson Gunnar W GW Skogholt Anne Heidi AH Smith Jennifer A JA Taylor Amy E AE Turman Constance C Willemsen Gonneke G Young Hannah H Young Kendra A KA Zajac Gregory J M GJM Zhao Wei W Zhou Wei W Bjornsdottir Gyda G Boardman Jason D JD Boehnke Michael M Boomsma Dorret I DI Chen Chu C Cucca Francesco F Davies Gareth E GE Eaton Charles B CB Ehringer Marissa A MA Esko Tõnu T Fiorillo Edoardo E Gillespie Nathan A NA Gudbjartsson Daniel F DF Haller Toomas T Harris Kathleen Mullan KM Heath Andrew C AC Hewitt John K JK Hickie Ian B IB Hokanson John E JE Hopfer Christian J CJ Hunter David J DJ Iacono William G WG Johnson Eric O EO Kamatani Yoichiro Y Kardia Sharon L R SLR Keller Matthew C MC Kellis Manolis M Kooperberg Charles C Kraft Peter P Krauter Kenneth S KS Laakso Markku M Lind Penelope A PA Loukola Anu A Lutz Sharon M SM Madden Pamela A F PAF Martin Nicholas G NG McGue Matt M McQueen Matthew B MB Medland Sarah E SE Metspalu Andres A Mohlke Karen L KL Nielsen Jonas B JB Okada Yukinori Y Peters Ulrike U Polderman Tinca J C TJC Posthuma Danielle D Reiner Alexander P AP Rice John P JP Rimm Eric E Rose Richard J RJ Runarsdottir Valgerdur V Stallings Michael C MC Stančáková Alena A Stefansson Hreinn H Thai Khanh K KK Tindle Hilary A HA Tyrfingsson Thorarinn T Wall Tamara L TL Weir David R DR Weisner Constance C Whitfield John B JB Winsvold Bendik Slagsvold BS Yin Jie J Zuccolo Luisa L Bierut Laura J LJ Hveem Kristian K Lee James J JJ Munafò Marcus R MR Saccone Nancy L NL Willer Cristen J CJ Cornelis Marilyn C MC David Sean P SP Hinds David A DA Jorgenson Eric E Kaprio Jaakko J Stitzel Jerry A JA Stefansson Kari K Thorgeirsson Thorgeir E TE Abecasis Gonçalo G Liu Dajiang J DJ Vrieze Scott S

Nature genetics 20190114 2

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evi ...[more]

PMID: 30643251

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Project description:The relationship between adolescent body mass index (BMI) and future risk for end-stage renal disease (ESRD) is not fully understood, nor is it known the extent to which this association is limited to diabetic ESRD. We evaluated the association between BMI in adolescence and the risk for all-cause, diabetic, and nondiabetic ESRD.Medical data about 1 194 704 adolescents aged 17 years who had been examined for fitness for military service between January 1, 1967, and December 31, 1997, were linked to the Israeli ESRD registry in this nationwide population-based retrospective cohort study. Incident cases of treated ESRD between January 1, 1980, and May 31, 2010, were included. Cox proportional hazards models were used to estimate the hazard ratio (HR) for treated ESRD among study participants for their BMI at age 17 years, defined in accord with the US Centers for Disease Control and Prevention BMI for age and sex classification.During 30 478 675 follow-up person-years (mean [SD], 25.51 [8.77] person-years), 874 participants (713 male and 161 female) developed treated ESRD, for an overall incidence rate of 2.87 cases per 100 000 person-years. Compared with adolescents of normal weight, overweight adolescents (85th to 95th percentiles of BMI) and obese adolescents (?95th percentile of BMI) had an increased future risk for treated ESRD, with incidence rates of 6.08 and 13.40 cases per 100 000 person-years, respectively. In a multivariate model adjusted for sex, country of origin, systolic blood pressure, and period of enrollment in the study, overweight was associated with an HR of 3.00 (95% CI, 2.50-3.60) and obesity with an HR of 6.89 (95% CI, 5.52-8.59) for all-cause treated ESRD. Overweight (HR, 5.96; 95% CI, 4.41-8.06) and obesity (HR, 19.37; 95% CI, 14.13-26.55) were strong and independent risk factors for diabetic ESRD. Positive associations of overweight (HR, 2.17; 95% CI, 1.71-2.74) and obesity (HR, 3.41; 95% CI, 2.42-4.79) with nondiabetic ESRD were also documented.Overweight and obesity in adolescents were associated with significantly increased risk for all-cause treated ESRD during a 25-year period. Elevated BMI constitutes a substantial risk factor for diabetic and nondiabetic ESRD.

Project description:AimsIn observational studies, type-2 diabetes is associated with increased risk of dementia; however, the causal nature of this association remains unanswered. In an unselected nationwide study of all Danes, we wanted to test whether type-2 diabetes is associated with dementia subtypes, and to test whether potential associations are of a causal nature.MethodsIn the current study of nationwide observational registry data in all Danes above the age of 65 years (n = 784 434) combined with genetic consortia data on 213 370 individuals, we investigated the associations between type-2 diabetes and Alzheimer's disease, vascular dementia, unspecified dementia and all-cause dementia, and whether observational associations were of a causal nature by applying a two-sample Mendelian randomisation strategy. We addressed key biases inherent in Mendelian randomisation approaches.ResultsImportant confounders (age, ethnicity, size of community, region, civil status and education level) were captured on all 784 434 individuals and adjusted for in the models. Multifactorial adjusted hazard ratios were 1.13 (1.06-1.21) for Alzheimer's disease, 1.98 (1.83-2.14) for vascular dementia, 1.53 (1.48-1.59) for unspecified dementia and 1.48 (1.44-1.53) for all-cause dementia in persons with type-2 diabetes v. without. Results were similar for men and women. The two-sample Mendelian randomisation estimate for the association between the genetic instrument and Alzheimer's disease was 1.04 (0.98-1.10), consistent with sensitivity estimates, addressing pleiotropy, measurement bias and weak instrument bias.ConclusionsIn a nationwide study of all Danes above the age of 65 years, we show that type-2 diabetes is associated with major subtypes of dementia - with particularly strong associations for vascular dementia and unspecified dementia - the two types of dementia with the most obvious vascular pathologies. Although the present two-sample Mendelian randomisation approach using genetic consortia data suggests that type-2 diabetes is not a direct cause of Alzheimer's disease, we were unable to test the causal nature of type-2 diabetes for vascular dementia and unspecified dementia, because no publicly available genetic consortia data yet exist for these dementia endpoints. The causal nature of type-2 diabetes for dementia with vascular pathologies is pivotal questions to solve for future public health recommendations and therapeutic advice.

Dataset Information

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Publications

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

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