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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:BackgroundChildhood adversity such as poverty, loss of a parent, and dysfunctional family dynamics may be associated with exposure to environmental and behavioral hazards, interfere with normal biological functions, and affect cancer care and outcomes. To explore this hypothesis, we assessed the cancer burden among young men and women exposed to adversity during childhood.MethodsWe undertook a population-based study using Danish nationwide register data on childhood adversity and cancer outcomes. Children who were alive and resident in Denmark until their 16th birthday were followed into young adulthood (16-38 years). Group-based multi-trajectory modelling was used to categorize individuals into five distinct groups: low adversity, early material deprivation, persistent material deprivation, loss/threat of loss, and high adversity. We assessed the association with overall cancer incidence, mortality, and five-year case fatality; and cancer specific outcomes for the four most common cancers in this age group in sex-stratified survival analyses.Findings1,281,334 individuals born between Jan 1, 1980, and Dec 31, 2001, were followed up until Dec 31, 2018, capturing 8229 incident cancer cases and 662 cancer deaths. Compared to low adversity, women who experienced persistent material deprivation carried a slightly lower risk of overall cancer (hazard ratio (HR) 0.90; 95% CI 0.82; 0.99), particularly due to malignant melanoma and brain and central nervous system cancers, while women who experienced high adversity carried a higher risk of breast cancer (HR 1.71; 95% CI 1.09; 2.70) and cervical cancer incidence (HR 1.82; 95% CI 1.18; 2.83). While there was no clear association between childhood adversity and cancer incidence in men, those men who had experienced persistent material deprivation (HR 1.72; 95% CI 1.29; 2.31) or high adversity (HR 2.27; 95% CI 1.38; 3.72) carried a disproportionate burden of cancer mortality during adolescence or young adulthood compared to men in the low adversity group.InterpretationChildhood adversity is associated with a lower risk of some subtypes of cancer and a higher risk of others, particular in women. Persistent deprivation and adversity are also associated with a higher risk of adverse cancer outcomes for men. These findings may relate to a combination of biological susceptibility, health behaviors and treatment-related factors.FundingNone.

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.

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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