Genome-wide Association Study of Smoking Initiation and Current Smoking

Department of Biological Psychology, Center for Neurogenomic and Cognitive Research, VU University Amsterdam, The Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.99). 04/2009; 84(3):367-79. DOI: 10.1016/j.ajhg.2009.02.001
Source: PubMed

ABSTRACT For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects. Significant genes that replicated in three independent samples (n = 405, 5810, and 1648) were visualized into a biologically meaningful network showing cellular location and direct interaction of their proteins. Several interesting groups of proteins stood out, including glutamate receptors (e.g., GRIN2B, GRIN2A, GRIK2, GRM8), proteins involved in tyrosine kinase receptor signaling (e.g., NTRK2, GRB14), transporters (e.g., SLC1A2, SLC9A9) and cell-adhesion molecules (e.g., CDH23). We conclude that a network-based genome-wide association approach can identify genes influencing smoking behavior.


Available from: Henning Tiemeier, May 12, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ribavirin is phosphorylated by adenosine kinase 1 (AK1) and cytosolic 5′-nucleotidase 2 and it is transported into cells by concentrative nucleoside transporters (CNT) 2/3, coded by SLC28A2/3 genes, and equilibrative nucleoside transporters (ENT) 1/2, coded by SLC29A1/2 genes. We evaluated the association of some polymorphisms of IL28B, SLC28A2/3, SLC29A1, ABCB1, NT5C2, AK1, HNF4α genes and ribavirin treatment outcome and pharmacokinetics after 4 weeks of therapy, in a cohort of HCV-1/4 Italian patients. Allelic discrimination was performed by real-time PCR; plasma concentrations were determined at the end of dosing interval (Ctrough) using an HPLC-UV method. Non response was negatively predicted by cryoglobulinemia and IL28B_rs12980275 AA genotype and positively by Metavir score; Metavir score, insulin resistance and SLC28A2_rs1060896 CA/AA and HNF4α_rs1884613 CC genotypes were negative predictive factors of SVR, while HCV viral load at baseline and IL28B_rs12980275 AA and rs8099917 TT genotypes positively predicted this outcome; RVR was negatively predicted by insulin resistance and positively by cryoglobulinemia and IL28B_rs12980275 AA genotype; Metavir score and insulin resistance were able to negatively predict EVR, whereas cryoglobulinemia and IL28B_rs12980275 AA genotype positively predicted it; at last, virological relapse was negatively predicted by IL28B_rs8099917 TT and AK1_rs1109374 TT genotypes, insulin resistance was a positive predictor factor. Concerning ribavirin pharmacokinetics, SLC28A2_rs11854488 TT was related to lower Ctrough levels; conversely patients with TC profile of SLC28A3_rs10868138 and SLC29A1_rs760370 GG genotype had higher ribavirin levels. These results might contribute to the clarification of mechanisms causing the individuality in the response to ribavirin containing therapy.
    Biomedecine [?] Pharmacotherapy 11/2014; 69. DOI:10.1016/j.biopha.2014.10.030 · 2.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To elucidate the effects of a controlled exposure to ethanol on gene expression, we studied lymphoblastoid cell lines (LCLs) from 21 alcoholics and 21 controls. We cultured each cell line for 24 h with and without 75 mM ethanol and measured gene expression using microarrays. Differences in expression between LCLs from alcoholics and controls included 13 genes previously identified as associated with alcoholism or related traits, including KCNA3, DICER1, ZNF415, CAT, SLC9A9, and PPARGC1B. The paired design allowed us to detect very small changes due to ethanol treatment: ethanol altered the expression of 37% of the probe sets (51% of the unique named genes) expressed in these LCLs, most by modest amounts. Ninety-nine percent of the named genes expressed in the LCLs were also expressed in brain. Key pathways affected by ethanol include cytokine, TNF, and NFκB signaling. Among the genes affected by ethanol were ANK3, EPHB1, SLC1A1, SLC9A9, NRD1, and SH3BP5, which were reported to be associated with alcoholism or related phenotypes in 2 genome-wide association studies. Genes that either differed in expression between alcoholics and controls or were affected by ethanol exposure are candidates for further study.
    Alcohol 09/2014; DOI:10.1016/j.alcohol.2014.07.004 · 2.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antisaccade deficits reflect abnormalities in executive function linked to various disorders including schizophrenia, externalizing psychopathology, and neurological conditions. We examined the genetic bases of antisaccade error in a sample of community-based twins and parents (N = 4,469). Biometric models showed that about half of the variance in the antisaccade response was due to genetic factors and half due to nonshared environmental factors. Molecular genetic analyses supported these results, showing that the heritability accounted for by common molecular genetic variants approximated biometric estimates. Genome-wide analyses revealed several SNPs as well as two genes-B3GNT7 and NCL-on Chromosome 2 associated with antisaccade error. SNPs and genes hypothesized to be associated with antisaccade error based on prior work, although generating some suggestive findings for MIR137, GRM8, and CACNG2, could not be confirmed.
    Psychophysiology 12/2014; 51(12):1272-84. DOI:10.1111/psyp.12347 · 3.18 Impact Factor