Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans.
- Authors
- Gelernter, Joel; Kranzler, Henry R; Sherva, Richard; Almasy, Laura; Herman, Aryeh I; Koesterer, Ryan; Zhao, Hongyu; Farrer, Lindsay A
- Year
- 2015
- Journal
- Biological psychiatry
- PMID
- 25555482
- DOI
- 10.1016/j.biopsych.2014.08.025
- PMCID
- PMC4386684
BACKGROUND: We report a genome-wide association study (GWAS) of nicotine dependence defined on the basis of scores on the FagerstrΓΆm Test for Nicotine Dependence in European-American (EA) and African-American (AA) populations. METHODS: Our sample, from the one used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime (2114 EA and 2602 AA subjects) and an additional 927 AA and 2003 EA subjects from the Study of Addiction: Genetics and Environment project [via the database of Genotypes and Phenotypes (dbGAP)]. GWAS analysis considered FagerstrΓΆm Test for Nicotine Dependence score as an ordinal trait, separately in each population and sample and by combining the results in meta-analysis. We also conducted analyses that were adjusted for other substance use disorder criteria in a single nucleotide polymorphism (SNP) subset. RESULTS: In EAs, one chromosome 7 intergenic region was genome-wide significant (GWS): rs13225753, p = 3.48 Γ 10(-8) (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 base pairs (minimal p = 4.74 Γ 10(-10)). Two chromosome 8 regions were associated: p = 4.45 Γ 10(-8) at DLC1 SNP rs289519 (unadjusted) and p = 1.10 Γ 10(-9) at rs6996964 (adjusted for other substances), located between CSGALNACT1 and INTS10. No GWS associations were observed at the chromosome 15 nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) previously associated with nicotine dependence and smoking quantity traits. TSNAX-DISC1 SNP rs821722 (p = 1.46 Γ 10(-7)) was the most significant result with substantial contributions from both populations; we previously identified DISC1 associations with opioid dependence. Pathway analysis identified association with nitric oxide synthase and adenosine monophosphate-activated protein kinase pathways in EAs. CONCLUSIONS: The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.
Trait distribution of FagerstrΓΆm Test for Nicotine Dependence (FTND) scores. AA, African American; EA, European American.
Manhattan plots. AA, African American; EA, European American.
Regional Manhattan plots. (A) Meta-analysis of the association results from single nucleotide polymorphisms (SNPs) in the 82.1 to 82.25 mega-base pair (MBP) region on chromosome 7 in Yale-UPenn + Study of Addiction: Genetics and Environment (SAGE) European American (EAs) with FagerstrΓΆm Test for Nicotine Dependence (FTND) score adjusted for co-occurring substance dependence severity. The SNPs are color coded according to R2, with the most significant SNP (rs13225753) shown in purple. The light blue line and right y axis show the observed recombination rate in the HapMap CEU samples. (B) Meta-analysis of the association results from SNPs in the 13.15 to 13.3 MBP region on chromosome 8 in Yale-UPenn + SAGE African Americans (AAs) with FTND score. The SNPs are color coded according to R2, with the most significant SNP (rs289519) shown in purple. The light blue line and right y axis show the observed recombination rate in the HapMap Yoruba in Ibadan, Nigeria (YRI) samples. (C) Meta-analysis of the association results from SNPs in the 19.55 to 19.7 MBP region on chromosome 8 in Yale-UPenn + SAGE AAs with FTND score adjusted for co-dependent substance dependence severity. The SNPs are color coded according to R2, with the most significant SNP (rs6996964) shown in purple. The light blue line and right y axis show the observed recombination rate in the HapMap YRI samples. (D) Meta-analysis of the association results from SNPs in the 45.3 to 45.6 MBP region on chromosome 14 in Yale-UPenn + SAGE AAs with FTND score. The SNPs are color coded according to R2, with the most significant SNP (rs144667340) shown in purple. The light blue line and right y axis show the observed recombination rate in the HapMap YRI samples.
Pathways associated with FagerstrΓΆm Test for Nicotine Dependence score in the European-American sample. (A) Endothelial nitric oxide synthase (eNOS) signaling. (B) Adenosine monophosphate-activated protein kinase (AMPK) signaling. AC, adenylate cyclase; ACC, acetyl coenzyme A carboxylase; Ach, acetylcholine; ACHR, acetylcholine receptor; ADP, adenosine diphosphate; ADR, adrenergic receptor; AICA, 5-Aminoimidazole-4-carboxamide; AK, adenylate kinase; AKT, v-akt murine thymoma viral oncogene homolog 1; AMP, adenosine 5-monophosphate; AQP, aquaporin; ATP, adenosine triphosphate; BDK, bradykinin; BDKR, bradykinin receptor; Ca2+, calcium; CALM, calmodulin; cAMP, cyclic adenosine monophosphate; CASP, caspase; CAT1, cationic amino acid transporter-1; CAV1, caveolin-1; CFTR, cystic fibrosis transmembrane conductance regulator; cGMP, cyclic guanosine monophosphate; CHIP, C-terminal Hsp70-interacting protein; CNG, cyclic nucleotide gateway; CPT, carnitine palmitoyltransferase; DAG, diacylglycerol; DNM2, dynamin 2; EDG, lysophosphatidic acid receptor; eF4EBP1, eukaryotic initiation factor 4e binding protein; ER, endoplasmic reticulum; ESR, estrogen receptor; FASN, fatty acid synthase; GLUT, glucose transporter; GPAT, glycerol-3-phosphate acyltransferase; GPCR, G protein-coupled receptor; GTP, guanosine triphosphate; GYS, glycogen synthase; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme-A reductase; HSL, hormone-sensitive lipase; HSP, heat shock protein; INS, insulin; INSR, insulin receptor; IP3, inositol 1,4,5-triphosphate; IP3R, inositol 1,4,5-triphosphate receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; MCD, Malonyl-CoA decarboxylase; MKK3, mitogen-activated protein kinase 3; mTOR, mammalian target of rapamycin; NO, nitric oxide; NOSIP, eNOS interacting protein; NOSTRIN, nitric oxide synthase traffic inducer; O2-, superoxide; PI3K, phosphoinositide kinase-3; PCAF, p300/CBP-associated factor; PDK1, phosphoinositide-dependent kinase-1; PFK, phosphofructokinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PP2A, protein phosphatase 2A; PP2C, protein phosphatase 2C; RTK, receptor tyrosine kinase; S-1P, sphingosine 1-phosphate; sGC, soluble guanylyl cyclase; SNF, sucrose non-fermentable; SRC, sarcoma; STK, serine/threonine kinase; SWI, switch; TSC, tumor suppressor complex; VEGF, vascular endothel growth factor; VEGFR, vascular endothel growth factor receptor; ZMP, zinc-dependent protease. (The networks were generated through the use of QIAGENβs Ingenuity Pathway Analysis (IPA[r]), QIAGEN Redwood City, California; www.qiagen.com/ingenuity).
| Name | Type |
|---|---|
| 1000 Genomes Project | cohort |
| β₯100 cigarettes smoked local | phenotype |
| AA | cohort |
| AA dataset local | cohort |
| adenosine monophosphate-activated protein kinase signaling local | drug |
| African American | cohort |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| AMPK | gene |
| Anti-inflammatory effects local | phenotype |
| ASW | cohort |
| bipolar disorder | phenotype |
| Blood pressure regulation local | phenotype |
| C14orf28 local | gene |
| C14ORF28 local | gene |
| CACNA2D1 | gene |
| calcium channel | drug |
| cannabis dependence | phenotype |
| cannabis use | phenotype |
| CCDC88A | gene |
| CEU | cohort |
| CHB | cohort |
| Chrna3 | gene |
| CHRNA5 | gene |
| Chrnb4 | gene |
| CHS | cohort |
| cigarettes | phenotype |
| CLM | gene |
| cocaine | phenotype |
| COGEND | cohort |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| control subjects | cohort |
| CSGALNACT1 local | gene |
| difficulty refraining from smoking in prohibited places local | phenotype |
| DISC1 | gene |
| DLC1 local | gene |
| DRD1 | gene |
| drug dependence | phenotype |
| Drug phenotypes local | phenotype |
| EA | cohort |
| EA dataset | cohort |
| EAs | cohort |
| endothelial nitric oxide synthase local | drug |
| European ancestry | cohort |
| FagerstrΓΆm Test for Nicotine Dependence | phenotype |
| FAM179B local | gene |
| FANCM local | gene |
| FIN | cohort |
| Finnish cohort | cohort |
| FKBP3 local | gene |
| FSCD | cohort |
| FTND | phenotype |
| FTND score | phenotype |
| GBR | cohort |
| GWAS | cohort |
| HapMap | cohort |
| IBS | cohort |
| illicit drug dependence | phenotype |
| illicit drug use | phenotype |
| Illumina Human1M array | drug |
| Illumina HumanOmni1-Quad v1.0 microarray | drug |
| Impute2 | drug |
| INTS10 local | gene |
| JPT | cohort |
| KLHL28 local | gene |
| least desired cigarette to give up local | phenotype |
| low MAF SNPs | variant |
| LWK | cohort |
| mu opioid receptor | drug |
| MXL | cohort |
| nicotine | drug |
| nicotine dependence | phenotype |
| nicotinic receptor cluster local | gene |
| Nondependent population local | phenotype |
| NOS3 | gene |
| opioid | drug |
| opioid dependence | phenotype |
| opioid sensitivity | phenotype |
| posttraumatic stress disorder | phenotype |
| PRPF39 local | gene |
| PUR | cohort |
| rs11633958 local | variant |
| rs13225753 local | variant |
| rs16969968 | variant |
| rs289519 local | variant |
| rs6996964 local | variant |
| rs821722 local | variant |
| SAGE | cohort |
| SAGE GWAS | cohort |
| schizophrenia | phenotype |
| single nucleotide polymorphisms | variant |
| smoking quantity | phenotype |
| smoking when ill or confined to bed local | phenotype |
| SNORD127 local | gene |
| SNP | cohort |
| substance use | phenotype |
| time to first cigarette after awakening local | phenotype |
| tobacco use | phenotype |
| TSI | cohort |
| TSNAX | gene |
| TSNAX-DISC1 local | gene |
| Vascular disorders local | phenotype |
| weight loss | phenotype |
| Yale-Penn | cohort |
| Yale-Penn GWAS local | cohort |
| YRI | cohort |
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