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ADH Gene Cluster Chromosome 4

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ADH Gene Cluster Chromosome 4 BEER William Hogarth’s view of alcohol related harm Lane 1. Genetic effects increasing susceptibility to alcoholism (eg cadherins associated with ADHD, aldehyde dehydrogensase 2, alcohol dehydrogenase genes etc). 2. Genetic susceptibility to cognitive damage (Wernicke Korsakov Syndrome). Thiamine transporter gene (SLC19A3) mutations associated with WKS. 3. Primary genetic effects from depression genes on alcoholism. eg SYNE1, TACR1 bipolar genes associated with Alcohol Dependence Syndrome. Explore other affective disorder genes eg ODZ4. 4. Genetic effects on criminality and dis-social personality disorder and secondary effects on increasing susceptibility to the Alcohol Dependence Syndrome. 5. Genetic effect on alcoholic liver disease discovered from the PNPLA3 and ZNF699 genes. Family studies of alcoholism, Cotton 1979 35 30 25 20 Per cent affected 15 10 5 0 Fathers Mothers Brothers Half sibs Aunts/Uncles Spouses Cotton,N.S. (1979): The Familial Incidence of Alcoholism. J. Stud. Alcohol 40, 89-116. FAMILY STUDIES OF ALCOHOLISM All family studies show very high rates in the 1st and 2nd degree relatives of alcohol dependence syndrome probands (eg 30%) This is evidence of genetic and cultural factors because 1st degree relatives should have a higher incidence of alcoholism than 2nd degree relatives if only genetic factors predominated Depression and alcoholism: Population and Family studies • About 60% to 70% of alcoholics have DSMIII major depressive disorder • Family and twin studies show increased rate of depression in twins/relatives of alcoholics who were not alcoholic • But rates of depression were significantly higher in those with alcoholism compared to relatives who were not alcoholic • Conclusion: Depression is both primary and secondary to alcoholism ie there is a 2 way interaction. Same applies to anxiety and criminality. Comorbidity between bipolar disorder and alcoholism • Most studies show that about 30% of bipolar affective disorder subjects have loosely defined alcoholism (RDC and DSMIII criteria) Twin Method, Dividing Genetic and Environmental Components of Human Traits eg alcohol consumption • Heritability (G) G = H2 = 2 (rmz- rdz) • Common Environment (CE) CE = C2 = 2 rdz – rmz • Specific Environment (SE) SE = 1- H2-CE = 1-G=(2rdz – rmz ) Concordance can be pair wise or proband wise, proband wise is better statistically but not used much Pair wise concordance in twin studies of alcoholism 80 70 60 50 40 MZ DZ 30 20 10 0 Kaij 1960 Hrubec Gurling Svikis 1988 Gottesman Koskenvuo Pickens 1981 1981 1988 1984 1991 Heritability of alcohol consumption and alcoholism from twin studies Heritability is variable in the different twin studies. Where twins are ascertained through early age of onset male cases with criminality then heritability is high eg 80% in Kaij’s Swedish twin study but overall genetic effects account for about 50% of the variance in both men and women. Depression and alcoholism: Twins • One alcoholism twin study showed greater concordance for depression than for alcoholism (Gurling et al 1984) • ie Twin pairs were more concordant for depression than for alcoholism and alcoholic cotwins had a higher rate of depression than non alcoholic cotwins. ie there was a genetic effect on depression and also increased depression caused by alcoholism. • CONCLUSION In the Maudsley twin sample depression was both primary and secondary to alcoholism • FAMILY STUDIES ALSO SUPPORT THE CONCLUSION THAT ALCOHOLISM IS BOTH Primary and secondary to alcoholism. Adoption studies of alcoholism Authors Influence of adoptive Increased incidence of family demonstrated alcoholism among adoptees with alcoholic biological parents Roe et al 1944 Male & Female - No Cadoret & Gath 1978 Males-Yes Females - No Males – Yes Females- Yes Cadoret et al 1985 Cadoret et al 1987 Males - Yes Females - Yes Goodwin et al 1973 Males-No Males - Yes Goodwin et al 1974 Goodwin et al 1977 Females-No Females - No Bohman et al 1978 Males-Yes Females-No Sigvardsson et al 1996 Males-Yes Females-No Adoption studies • Original studies done in Denmark and Sweden. • Child adopted out. • Father alcoholic: 18% sons affected. • Father non-alcoholic: 5% sons affected. • Daughters less affected. CLONINGER’ S CLASSIFICATION OF “ALCOHOLISM” Derived from two adoption studies in Sweden which gave the same genetic and environmental effects TYPE I TYPE II ‘Milieu Limited’ ‘Male Limited’ DRINKING PATTERN Loss of control Inability to abstain SEX Male & Female Male HERITABILITY Parents mild or non-abusers Highly heritable CRIMINALITY No association Associated POST-NATAL Determines severity May influence severity ENVIRONMENT Frequency SEVERITY Usually mild Moderate/Severe AGE OF ONSET >25 years <25 years Swedish adoption studies Sigvardsson, S; Bohman, M.et al Replication of the Stockholm Adoption study of alcoholism: confirmatory cross-fostering analysis. Archives of general Psychiatry 53:681–687, 1996. Genes and environment for UNIPOLAR affective disorder from all twin studies G 72% CE <1% SE 29% Genes and environmental variance for BIPOLAR DISORDER from all twin studies combined Genes (G) 82% Family (CE) 1% Specific Environment (SE) 19% Bipolar and unipolar affective disorder genes associated with alcoholism Bipolar Gene Test p Source C12/Slynar Allelic Association 0.006 UCL TRPM2 Allelic Association 0.04 UCL SYNE1 Allelic Association 0.00005 Treutlein et al 2009 SYNE1 Allelic Association 0.02 Edenberg et al 2010 P2RX7 Allelic Association 0.002 WCPG abstract CHRM2 Allelic Association 0.003 Luo et al 2005 TACR1 (NK1R)* Allelic Association 0.009 Sharp et al 2013 GRM3 (mGlur3)* Allelic Association 0.08 Kandaswamy et al 2013 Spectrin repeat SYNE1/CPG2 region associated with BIPOLAR disorder CGP2 CPG2 is a brain-specific splice variant of SYNE1 Nonsynonymous SNP with strong association 21 and bipolar disorder George, D. T., J. Gilman, et al. (2008). "Neurokinin 1 receptor antagonism as a possible therapy for alcoholism." Science 319(5869): 1536-1539. Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder Radhika Kandaswamy, MSc, MPhil, PhD; Andrew McQuillin, PhD; Sally Sharp, PhD; Alessia Fiorentino, PhD; Adebayo Anjorin, MBchB, MSc, MRCPsych; Robert A. Blizard, MSc, MSc; David Curtis, MBBS, MD, PhD, MRCPsych; Hugh M. D. Gurling, MBBS, MD, MPhil, FRCPsych Jama Psychiatry, April 10th 2013 GRM3 ALSO SIGNIFICANTLY ASSOCIATED WITH THE ALCOHOL DEPENDENCE SYNDROME at UCL Effects of GRM2/3 agonists GRM2/3 agonists cause reductions in the evoked release of glutamate and concomitant reduction on post-synaptic glutamate-mediated excitations (Schoepp, 2001) Presynaptic effects GRM2/3 receptors not in the synaptic junction ie they a presynaptic (Cartmell and Schoepp, 2000), they may monitor glutamate escaping from junction and prevent pathological glutamate excitation Postsynaptic effects GRM2/3 hyperpolarize cells thus decreasing excitability (Tamaru et al, 2001) Neale, J. H., R. T. Olszewski, et al. (2011). "Advances in understanding the peptide neurotransmitter NAAG and appearance of a new member of the NAAG neuropeptide family." J Neurochem 118(4): 490-498. Chromosome 4 ADH gene cluster strongly associated with alcoholism in many studies UCL SNPs at ADH gene cluster associated with ADS Significance Odds SNP ID Nearest gene Function Position Average MPP* (P value) ratio rs3133155 ADH1B near 3' UTR 100227212 0.95 3.0E-04 1.2 rs28914794 ADH1B near 3' UTR 100227288 0.99 5.5E-04 0.52 rs28914793 ADH1B near 3' UTR 100227327 0.83 7.1E-03 0.93 rs1042026 ADH1B 3' UTR 100228466 0.80 8.8E-04 1.1 rs17033 ADH1B 3' UTR 100228945 0.99 5.1E-04 0.54 rs1789882 ADH1B synonymous 100235053 0.95 3.1E-04 1.2 rs1229984b ADH1B missense 100239319 0.97 2.7E-05 0.51 rs1159918 ADH1B near 5' UTR 100243009 0.93 2.0E-04 1.3 rs2070898 ADH1B near 5' UTR 100243297 0.79 1.1E-03 1.1 rs2070897 ADH1B near 5' UTR 100243310 0.94 2.9E-04 1.3 rs74871662 ADH1B near 5' UTR 100243445 0.93 3.0E-04 1.3 rs28913903 ADH1B near 5' UTR 100243480 0.65 7.6E-01 1.0 rs1229982 ADH1B near 5' UTR 100243932 0.87 3.5E-06 1.1 rs3811802 ADH1B near 5' UTR 100244221 0.84 2.1E-01 1.1 rs3811801 ADH1B near 5' UTR 100244319 0.58 5.5E-01 0.98 rs9307239 Intergenic unknown 100246937 0.73 2.3E-06 1.1 rs1789891b Intergenic unknown 100250419 0.95 5.6E-05 1.3 rs13117923 Intergenic unknown 100252198 0.78 1.0E-05 0.92 rs67631357 Intergenic unknown 100253563 0.78 8.4E-06 0.92 rs2298753 ADH1C 3' UTR 100257907 0.99 4.8E-04 1.3 rs1614972 ADH1C intronic 100258155 0.53 6.0E-05 0.90 rs698c ADH1C missense 100260789 0.98 1.5E-03 1.3 rs2241894 ADH1C synonymous 100266133 0.74 9.6E-03 0.89 rs1789915 ADH1C synonymous 100266371 0.97 4.9E-04 0.75 rs283413c ADH1C Nonsense 100268190 0.88 7.5E-04 1.1 rs13118443 ADH1C intronic 100269373 0.98 8.8E-05 0.77 rs34761493 ADH1C intronic 100273170 0.80 9.4E-05 0.94 TWO INDEPENDENT EFFECTS ON ALCOHOLISM FROM ADH1C GENE IN UCL alcoholism case control sample Table 1 Conditional testing of the independence of the effects between the ADH1C coding variants and the primary ADH SNPs genotyped Significance (P value) ADH 1C SNP Annotation rs1229984 rs1789891 rs698 ADH1C Ile350Val 0.013 0.19 rs1693482 ADH1C Arg272Gln 0.0012 0.06 rs283413 ADH1C Gly78STOP 0.25 0.0023 The likelihood ratio test P value is a measure of the independence of the allelic association signal, between the two SNPs under comparison. The greater the significance of the P value the more likely that the two SNPs under investigation are not contributing independently to the allelic association signal Starch Gel electrophoresis of ALDH2-2 mutation effect on substrate metabolism Propionaldehyde Benzaldehyde Developmental trajectory and environmental moderation of the effect of ALDH2 polymorphism on alcohol use. Irons DE, Iacono WG, Oetting WS, McGue M.
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