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

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

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

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . 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

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

Epidemiology of hairy cell leukemia in Iceland

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldINTRODUCTION: Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder. Previous epidemiological studies have mainly focused on cases derived from single institutions or from localized cancer registries. This is the first study in which all cases diagnosed nationwide over a long period of time in a well defined population are analysed. We report the epidemiology of all HCL patients in Iceland, their clinical characteristics, treatment and follow-up. PATIENTS AND METHODS:: All patients diagnosed with HCL in Iceland over a 20 year period, were included in this study. Data was collected retrospectively. RESULTS: Sixteen patients, 13 males and three females were diagnosed with HCL in Iceland from 1981-2000, giving a mean incidence of 4.7/million/year (95% CI: 2.7-7.6) in the population 20 years and older. Eleven patients were treated with a purine analogue, 10 of whom achieved CR. One other patient obtained CR following splenectomy and IFN, giving a total CR rate of 69%. Three other patients (19%) obtained PR, giving a total response rate of 88%. One patient had a variant of HCL and did not respond to any therapy and one patient died of sepsis before any chemotherapy could be given. Six patients with HCL have died, one from complications of HCL. Three patients developed a second malignancy (19%). CONCLUSIONS: The mean incidence of HCL in Iceland is 4.7/million/year. This is slighty higher than the reported incidence in England and Wales, although not significantly higher. The incidence is based on a nationwide information from a well defined stable and racially homogenous island population. Other results are in accordance with previously published studies

A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.Lung GO Sequencing Project HL-102923 WHI Sequencing Project HL-102924 Broad GO Sequencing Project HL-102925 Seattle GO Sequencing Project HL-102926 Heart GO Sequencing Project HL-10301

Prevalence and early-life risk factors of school age allergic multimorbidity - the EuroPrevall-iFAAM birth cohort

BACKGROUND: Coexistenceofchildhoodasthma,eczemaandallergicrhinitisishigherthancanbeexpectedbychance,suggestingacommonmechanism.Dataonallergicmultimorbidityfromapan-European,population-basedbirthcohortstudyhasbeenlacking. This study compares the prevalence and early-life risk factors of these diseases in European primary school children.METHODS: IntheprospectivemulticentreobservationalEuroPrevall/iFAAMbirthcohortstudyweusedstandardizedquestionnairesonsocio-demographics,medicalhistory,parentalallergiesandlifestyle,andenvironmentalexposuresatbirth,12and24months.Atprimaryschoolage,parentsansweredISAAC-basedquestionsoncurrentasthma,rhinitisandeczema.Allergicmultimorbiditywasdefinedasthecoexistenceofatleasttwoofthese.RESULTS: From10,563childrenrecruitedatbirthin8studycentres,weincludeddatafrom5,572children(meanage8.2years;51.8%boys).Prevalenceestimateswere:asthma8.1%,allergicrhinitis13.3%,eczema12.0%.Allergicmultimorbiditywasseenin7.0%ofthewholecohort,rangingfrom1.2%(Athens,Greece)to10.9%(Madrid,Spain). Riskfactorsforallergicmultimorbidity, identified with AICc,includedfamily-allergy-score, oddsratio(OR)1.50 (95% CI 1.32-1.70)perstandarddeviation;early-lifeallergysymptoms, OR2.72 (2.34-3.16)foreachsymptom;andcaesareanbirth, OR1.35 (1.04-1.76).Femalegender, OR0.72 (0.58-0.90);oldersiblings,OR0.79 (0.63-0.99);andday-care, OR0.81 (0.63-1.06)wereprotectivefactors.CONCLUSION: AllergicmultimorbidityshouldberegardedasanimportantchronicchildhooddiseaseinEurope.Someoftheassociatedearly-lifefactorsaremodifiableandmaybeconsideredforpreventionstrategies.</p

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

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

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

Files include summary statistics for associations with each phenotype: Drinks per week, Cigarettes per day, Smoking initiation, Smoking cessation, and Age of initiation. Details for each file can be found in the readme file or in the article's Supplementary Text.We conducted a meta-analysis of over 30 genome wide association studies (GWAS) in over 1.2 million participants with European ancestry on nicotine and substance use. Specifically, we targeted different stages and kinds of substance use from initiation (smoking initiation and age of regular smoking initiation) to regular use (drinks per week and cigarettes per day) to cessation (smoking cessation). The GWAS included have all been imputed to Haplotype Reference Consortium, 1000 Genomes or a combination including more specific reference panels. The studies are then meta-analyzed using sample size, allele frequencies and the imputation quality score as weight. Here we present the final set of filtered meta-analysis summary statistics as presented in the paper (https://doi.org/10.1038/s41588-018-0307-5) excluding 23andMe. As per requirement and to ease dissemination of our results for other scientific endeavors, we are sharing our results here to facilitate downloading.R01DA037904R01HG008983R21DA04017