title: A multiancestry study identifies novel genetic associations with CHRNA5 methylation in human brain and risk of nicotine dependence.
abstract: Nicotine dependence is influenced by chromosome 15q25.1 single nucleotide polymorphisms (SNPs), including the missense SNP rs16969968 that alters function of the α5 nicotinic acetylcholine receptor (CHRNA5) and noncoding SNPs that regulate CHRNA5 mRNA expression. We tested for cis-methylation quantitative trait loci (cis-meQTLs) using SNP genotypes and DNA methylation levels measured across the IREB2-HYKK-PSMA4-CHRNA5-CHRNA3-CHRNB4 genes on chromosome 15q25.1 in the BrainCloud and Brain QTL cohorts [total N = 175 European-Americans and 65 African-Americans (AAs)]. We identified eight SNPs that were significantly associated with CHRNA5 methylation in prefrontal cortex: P ranging from 6.0 × 10(-10) to 5.6 × 10(-5). These SNP-methylation associations were also significant in frontal cortex, temporal cortex and pons: P ranging from 4.8 × 10(-12) to 3.4 × 10(-3). Of the eight cis-meQTL SNPs, only the intronic CHRNB4 SNP rs11636753 was associated with CHRNA5 methylation independently of the known SNP effects in prefrontal cortex, and it was the most significantly associated SNP with nicotine dependence across five independent cohorts (total N = 7858 European ancestry and 3238 AA participants): P = 6.7 × 10(-4), odds ratio (OR) [95% confidence interval (CI)] = 1.11 (1.05-1.18). The rs11636753 major allele (G) was associated with lower CHRNA5 DNA methylation, lower CHRNA5 mRNA expression and increased nicotine dependence risk. Haplotype analyses showed that rs11636753-G and the functional rs16969968-A alleles together increased risk of nicotine dependence more than each variant alone: P = 3.1 × 10(-12), OR (95% CI) = 1.32 (1.22-1.43). Our findings identify a novel regulatory SNP association with nicotine dependence and connect, for the first time, previously observed differences in CHRNA5 mRNA expression and nicotine dependence risk to underlying DNA methylation differences.
authors.affiliation: Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, dhancock@rti.org.
authors.forename: Dana B
authors.initials: DB
authors.lastname: Hancock
authors.affiliation: Department of Neuroscience and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jen-Chyong
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Research Computing Division.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Gaddis
authors.affiliation: Research Computing Division.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Levy
authors.affiliation: Department of Genetics.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Saccone
authors.affiliation: Department of Integrative Physiology, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Stitzel
authors.affiliation: Department of Neuroscience and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA and.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.affiliation: Fellow Program and Behavioral Health and Criminal Justice Division, Research Triangle Institute (RTI) International, Research Triangle Park, NC 27709, USA.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Johnson
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D012306:Risk; D014029:Tobacco Use Disorder / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C447158:CHRNA5 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011978:Receptors, Nicotinic