Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use. Brazel, D. M., Jiang, Y., Hughey, J. M., Turcot, V., Zhan, X., Gong, J., Batini, C., Weissenkampen, J. D., Liu, M., CHD Exome+ Consortium, Consortium for Genetics of Smoking Behaviour, Barnes, D. R., Bertelsen, S., Chou, Y., Erzurumluoglu, A. M., Faul, J. D., Haessler, J., Hammerschlag, A. R., Hsu, C., Kapoor, M., Lai, D., Le, N., de Leeuw, C. A., Loukola, A., Mangino, M., Melbourne, C. A., Pistis, G., Qaiser, B., Rohde, R., Shao, Y., Stringham, H., Wetherill, L., Zhao, W., Agrawal, A., Bierut, L., Chen, C., Eaton, C. B., Goate, A., Haiman, C., Heath, A., Iacono, W. G., Martin, N. G., Polderman, T. J., Reiner, A., Rice, J., Schlessinger, D., Scholte, H. S., Smith, J. A., Tardif, J., Tindle, H. A., van der Leij, A. R., Boehnke, M., Chang-Claude, J., Cucca, F., David, S. P., Foroud, T., Howson, J. M. M., Kardia, S. L. R., Kooperberg, C., Laakso, M., Lettre, G., Madden, P., McGue, M., North, K., Posthuma, D., Spector, T., Stram, D., Tobin, M. D., Weir, D. R., Kaprio, J., Abecasis, G. R., Liu, D. J., & Vrieze, S. Biological Psychiatry, 85(11):946–955, 2019.
doi abstract bibtex

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

@article{brazel_exome_2019,
	title = {Exome {Chip} {Meta}-analysis {Fine} {Maps} {Causal} {Variants} and {Elucidates} the {Genetic} {Architecture} of {Rare} {Coding} {Variants} in {Smoking} and {Alcohol} {Use}},
	volume = {85},
	issn = {1873-2402},
	doi = {10.1016/j.biopsych.2018.11.024},
	abstract = {BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.
METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.
RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1\% to 2.2\% of phenotypic variance, reflecting 11\% to 18\% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95\% credible intervals.
CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.},
	language = {eng},
	number = {11},
	journal = {Biological Psychiatry},
	author = {Brazel, David M. and Jiang, Yu and Hughey, Jordan M. and Turcot, Valérie and Zhan, Xiaowei and Gong, Jian and Batini, Chiara and Weissenkampen, J. Dylan and Liu, MengZhen and {CHD Exome+ Consortium} and {Consortium for Genetics of Smoking Behaviour} and Barnes, Daniel R. and Bertelsen, Sarah and Chou, Yi-Ling and Erzurumluoglu, A. Mesut and Faul, Jessica D. and Haessler, Jeff and Hammerschlag, Anke R. and Hsu, Chris and Kapoor, Manav and Lai, Dongbing and Le, Nhung and de Leeuw, Christiaan A. and Loukola, Anu and Mangino, Massimo and Melbourne, Carl A. and Pistis, Giorgio and Qaiser, Beenish and Rohde, Rebecca and Shao, Yaming and Stringham, Heather and Wetherill, Leah and Zhao, Wei and Agrawal, Arpana and Bierut, Laura and Chen, Chu and Eaton, Charles B. and Goate, Alison and Haiman, Christopher and Heath, Andrew and Iacono, William G. and Martin, Nicholas G. and Polderman, Tinca J. and Reiner, Alex and Rice, John and Schlessinger, David and Scholte, H. Steven and Smith, Jennifer A. and Tardif, Jean-Claude and Tindle, Hilary A. and van der Leij, Andries R. and Boehnke, Michael and Chang-Claude, Jenny and Cucca, Francesco and David, Sean P. and Foroud, Tatiana and Howson, Joanna M. M. and Kardia, Sharon L. R. and Kooperberg, Charles and Laakso, Markku and Lettre, Guillaume and Madden, Pamela and McGue, Matt and North, Kari and Posthuma, Danielle and Spector, Timothy and Stram, Daniel and Tobin, Martin D. and Weir, David R. and Kaprio, Jaakko and Abecasis, Gonçalo R. and Liu, Dajiang J. and Vrieze, Scott},
	year = {2019},
	pmid = {30679032},
	pmcid = {PMC6534468},
	keywords = {Alcohol, Alcohol Drinking, Behavioral genetics, Databases, Genetic, Exome, GWAS, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Heritability, Humans, Nicotine, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Smoking, Tobacco},
	pages = {946--955},
}

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