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 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.





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Publication Info

Saunders, Gretchen RB, Xingyan Wang, Fang Chen, Seon-Kyeong Jang, Mengzhen Liu, Chen Wang, Shuang Gao, Yu Jiang, et al. (2022). Genetic diversity fuels gene discovery for tobacco and alcohol use. Nature, 612(7941). pp. 720–724. 10.1038/s41586-022-05477-4 Retrieved from

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Allison Elizabeth Ashley-Koch

Professor in Medicine

My work focuses on the dissection of human traits using multi-omic technologies (genetics, epigenetics, metabolomics and proteomics).  I am investigating the basis of several neurological and psychiatric conditions such as neural tube defects and post-traumatic stress disorder. I also study modifiers of sickle cell disease.


Marilyn Jo Telen

Wellcome Clinical Distinguished Professor of Medicine in Honor of R. Wayne Rundles, M.D.

Dr. Telen is recognized as an expert in the biochemistry and molecular genetics of blood group antigens and the pathophysiological mechanisms of vaso-occlusion in sickle cell disease. She is the Director of the Duke Comprehensive Sickle Cell Center.

Dr. Telen's laboratory focuses on structure/function analysis of membrane proteins expressed by erythroid cells, as well as the role of these proteins in non-erythroid cells. Proteins are also studied in transfectant systems, and research focuses especially on adhesion receptors. The goals of this work are (1) to understand the mechanism and role of red cell adhesion to leukocytes and endothelium in sickle cell disease; (2) to understand the signaling mechanisms leading to activation (and inactivation) of red cell adhesion molecules; (3) to understand the molecular basis of blood group antigen expression, and (4) to understand the interactions of erythroid membrane proteins with other cells and with extracellular matrix..

Recent investigations have focused on the role of signaling pathways in the upregulation of sickle red cell adhesion. Present studies include (1) investigation of beta-adrenergic signaling pathway responsible for activation of B-CAM/LU and LW adhesion receptors; (2) understanding how nitric oxide and ATP downregulate sickle red cell adhesion; (3) studying the effect of these processes in animal models.

Dr. Telen is also involved in a large multicenter study looking for genetic polymorphisms that affect clinical outcomes in sickle cell disease, as well as a multi-center study investigating the mechanisms and treatment of pulmonary hypertension in sickle cell disease.

Key Words:

Adhesion molecules
Erythrocyte membrane
Sickle cell disease
Transfusion medicine
Genetic polymorphisms

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