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Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

ABSTRACT: Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N?=?33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (r_g?=?0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.

SUBMITTER: Quach BC

PROVIDER: S-EPMC7642344 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

Quach Bryan C BC Bray Michael J MJ Gaddis Nathan C NC Liu Mengzhen M Palviainen Teemu T Minica Camelia C CC Zellers Stephanie S Sherva Richard R Aliev Fazil F Nothnagel Michael M Young Kendra A KA Marks Jesse A JA Young Hannah H Carnes Megan U MU Guo Yuelong Y Waldrop Alex A Sey Nancy Y A NYA Landi Maria T MT McNeil Daniel W DW Drichel Dmitriy D Farrer Lindsay A LA Markunas Christina A CA Vink Jacqueline M JM Hottenga Jouke-Jan JJ Iacono William G WG Kranzler Henry R HR Saccone Nancy L NL Neale Michael C MC Madden Pamela P Rietschel Marcella M Marazita Mary L ML McGue Matthew M Won Hyejung H Winterer Georg G Grucza Richard R Dick Danielle M DM Gelernter Joel J Caporaso Neil E NE Baker Timothy B TB Boomsma Dorret I DI Kaprio Jaakko J Hokanson John E JE Vrieze Scott S Bierut Laura J LJ Johnson Eric O EO Hancock Dana B DB

Nature communications 20201103 1

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits ...[more]

PMID: 33144568

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Project description:BackgroundObservational studies have associated obesity with an increased risk of multiple sclerosis (MS). However, the role of genetic factors in their comorbidity remains largely unknown. Our study aimed to investigate the shared genetic architecture underlying obesity and MS.MethodsBy leveraging data from genome-wide association studies, we investigated the genetic correlation of body mass index (BMI) and MS by linkage disequilibrium score regression and genetic covariance analyser. The casualty was identified by bidirectional Mendelian randomisation. Linkage disequilibrium score regression in specifically expressed genes and multimarker analysis of GenoMic annotation was utilised to explore single-nucleotide polymorphism (SNP) enrichment at the tissue and cell-type levels. Shared risk SNPs were derived using cross-trait meta-analyses and Heritability Estimation from Summary Statistics. We explored the potential functional genes using summary-data-based Mendelian randomization (SMR). The expression profiles of the risk gene in tissues were further examined.FindingsWe found a significantly positive genetic correlation between BMI and MS, and the causal association of BMI with MS was supported (β = 0.22, P = 8.03E-05). Cross-trait analysis yielded 39 shared risk SNPs, and the risk gene GGNBP2 was consistently identified in SMR. We observed tissue-specific level SNP heritability enrichment for BMI mainly in brain tissues for MS in immune-related tissues, and cell-type-specific level SNP heritability enrichment in 12 different immune cell types in brain, spleen, lung, and whole blood. The expressions of GGNBP2 were significantly altered in the tissues of patients with obesity or MS compared to those of control subjects.InterpretationOur study indicates the genetic correlation and shared risk genes between obesity and MS. These findings provide insights into the potential mechanisms behind their comorbidity and the future development of therapeutics.FundingThis work was funded by the National Natural Science Foundation of China (82171698, 82170561, 81300279, and 81741067), the Program for High-level Foreign Expert Introduction of China (G2022030047L), the Natural Science Foundation for Distinguished Young Scholars of Guangdong Province (2021B1515020003), Natural Science Foundation of Guangdong Province (2022A1515012081), the Foreign Distinguished Teacher Program of Guangdong Science and Technology Department (KD0120220129), the Climbing Programme of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital (DFJH201803, KJ012019099, KJ012021143, and KY012021183), and in part by VA Clinical Merit and ASGE clinical research funds (FWL).

Dataset Information

Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

Publications

Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

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