Alcohol abuse is a major public health problem worldwide. Understanding the molecular mechanisms that control regular drinking may help to reduce hazards of alcohol consumption. While immunological mechanisms have been related to alcohol drinking, most studies reported changes in immune function that are secondary to alcohol use. In this report, we analyse how the gene "TRAF family member-associated NF-kappa B activator" (TANK) affects alcohol drinking behavior. Based on our recent discovery in a large GWAS dataset that suggested an association of TANK, SNP rs197273, with alcohol drinking, we report that SNP rs197273 in TANK is associated both with gene expression (P = 1.16 x 10(-19)) and regional methylation (P = 5.90 x 10(-25)). A tank knock out mouse model suggests a role of TANK in alcohol drinking, anxiety-related behavior, as well as alcohol exposure induced activation of insular cortex NF-kappa B. Functional and structural neuroimaging studies among up to 1896 adolescents reveal that TANK is involved in the control of brain activity in areas of aversive interoceptive processing, including the insular cortex, but not in areas related to reinforcement, reward processing or impulsiveness. Our findings suggest that the cortical neuroimmune regulator TANK is associated with enhanced aversive emotional processing that better protects from the establishment of alcohol drinking behavior.
[1]Friedrich Alexander Univ Erlangen Nuremberg, Univ Clin, Dept Psychiat & Psychotherapy, Sect Addict Med, Schwabachanlage 6, D-91054 Erlangen, Germany;
[2]Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Stratified Med PONS, De Crespigny Pk, London SE5 8AF, England;
[3]Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, De Crespigny Pk, London SE5 8AF, England;
[4]Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA;
[5]Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA;
[6]NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20824 USA;
[7]Boston Univ, Sch Publ Hlth, 715 Albany St, Boston, MA 02118 USA;
[8]Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England;
[9]Friedrich Alexander Univ Erlangen Nuremberg, Inst Biochem & Mol Med, Fahrstr 17, D-91054 Erlangen, Germany;
[10]Osaka Univ, Microbial Dis Res Inst, World Premier Int Immunol Frontiern Res Ctr, Lab Host Def, 1-1 Yamadaoka, Suita, Osaka 5650871, Japan;
[11]Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, J5, D-68159 Mannheim, Germany;
[12]Trinity Coll Dublin, Sch Med, Discipline Psychiat, Jamess St, Dublin 8, Ireland;
[13]Trinity Coll Dublin, Trin Coll Inst Neurosci, Jamess St, Dublin 8, Ireland;
[14]Univ Med Ctr Hamburg Eppendorf, House W34,3 OG,Martinistr 52, D-20246 Hamburg, Germany;
[15]Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Cognit & Clin Neurosci, J5, D-68159 Mannheim, Germany;
[16]Univ Mannheim, Sch Social Sci, Dept Psychol, D-68131 Mannheim, Germany;
[17]Univ Paris Saclay, CEA, NeuroSpin, F-91191 Gif Sur Yvette, France;
[18]Univ Vermont, Dept Psychiat, Burlington, VT 05405 USA;
[19]Univ Vermont, Dept Psychol, Burlington, VT 05405 USA;
[20]Univ Nottingham, Sch Phys & Astron, Sir Peter Mansfield Imaging Ctr, Univ Pk, Nottingham NG7 2QX, England;
[21]Charite Univ Med Berlin, Campus Charite Mitte, Dept Psychiat & Psychotherapy, Charitepl 1, D-10117 Berlin, Germany;
[22]PTB, Braunschweig, Germany;
[23]PTB, Abbestr 2-12, D-10587 Berlin, Germany;
[24]Univ Paris Saclay, Univ Paris Sud, INSERM, Unit 1000,Neuroimaging & Psychiat,DIGITEO Labs, Rue Noetzlin, F-91190 Gif Sur Yvette, France;
[25]Univ Paris Saclay, Univ Paris Sud, INSERM, Unit 1000,Neuroimaging & Psychiat, Gif Sur Yvette, France;
[26]Hop La Pitie Salpetriere, AP HP, Dept Child & Adolescent Psychiat, 47-83 Blvd Hop, F-75013 Paris, France;
[27]Orsay Hosp, Psychiat Dept 91G16, Orsay, France;
[28]Univ Paris Sud, Sch Med, INSERM, Unit 1000,Neuroimaging & Psychiat, Gif Sur Yvette, France;
[29]Univ Toronto, Rotman Res Inst, 3560 Bathurst St, Toronto, ON M6A 2E1, Canada;
[30]Univ Toronto, Dept Psychol, 3560 Bathurst St, Toronto, ON M6A 2E1, Canada;
[31]Univ Toronto, Dept Psychiat, 3560 Bathurst St, Toronto, ON M6A 2E1, Canada;
[32]Univ Med Ctr Gottingen, Dept Child & Adolescent Psychiat & Psychotherapy, von Siebold Str 5, D-37075 Gottingen, Germany;
[33]Med Univ Vienna, Clin Child & Adolescent Psychiat, Wahringer Gurtel 18-20, A-1090 Vienna, Austria;
[34]Tech Univ Dresden, Dept Psychiat, Chemnitzer Str 46a, D-01187 Dresden, Germany;
[35]Tech Univ Dresden, Neuroimaging Ctr, Chemnitzer Str 46a, D-01187 Dresden, Germany;
[36]Aras Phiarsaigh Trinity Coll Dublin, Sch Psychol, Dublin 2, Ireland;
[37]Aras Phiarsaigh Trinity Coll Dublin, Global Brain Hlth Inst, Dublin 2, Ireland;
[38]Uppsala Univ, Dept Pharmaceut, Biosci, Div Biol Res Drug Dependence, Husargatan 3,591, SE-75237 Uppsala, Sweden;
[39]Minist Educ, Key Lab Metab & Mol Med, Shanghai, Peoples R China;
[40]Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Shanghai, Peoples R China;
[41]Univ Leipzig, Dept Anaesthesiol & Intens Care Med, Liebigstr 20, D-04103 Leipzig, Germany
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