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.

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 injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. 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.

ObjectiveChildhood trauma is recognized as an important risk factor in suicidal ideation, however it is not fully understood how the different types of childhood maltreatment influence suicidal ideation nor what variables mediate the relationship between childhood trauma and suicidal ideation. This study examined the path from childhood trauma to suicidal ideation, including potential mediators.MethodsA sample of 211 healthy adults completed the Childhood Trauma Questionnaire (CTQ), Beck scale for Suicidal Ideation (BSI), Functional Social Support Questionnaire (FSSQ) and Hospital Anxiety and Depression Scale (HADS). Path analysis was used to investigate the relationship among study variables.ResultsOf the several types of childhood maltreatment we considered, only childhood sexual abuse directly predicted suicidal ideation (β=0.215, p=0.001). Childhood physical abuse (β=0.049, 95% confidence interval: 0.011–0.109) and childhood emotional abuse (β=0.042, 95% confidence interval: 0.001–0.107) indirectly predicted suicidal ideation through their association with anxiety. Childhood neglect indirectly predicted suicidal ideation through association with perceived social support (β=0.085, 95% confidence interval: 0.041–0.154).ConclusionOur results confirmed that childhood sexual abuse is a strong predictor of suicidal ideation. Perceived social support mediated the relationship between suicidal ideation and neglect. Anxiety fully mediated the relationship between suicidal ideation and both physical abuse and emotional abuse. Interventions to reduce suicidal ideation among survivors of childhood trauma should focus on anxiety symptoms and attempt to increase their social support.