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Functional alleles & intermediate phenotypes in alcoholism and dyscontrol disorders David Goldman davidgoldman@mail.nih.gov
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1935-2006
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Begleiter, H., and Platz, A. (1969). Evoked potentials: Modifications by conditioning. Science 166:769-771. Begleiter, H., Porjesz, B., Yerre, C., and Kissin, B. (1973). Evoked potential correlates of expected stimulus intensity. Science 179(4075):814-816. Begleiter, H., and Porjesz, B. (1975). Evoked brain potentials as indicators of decision-making. Science 187:754-755. Begleiter, H., and Porjesz, B. (1975). On evoked potentials, cognition, and memory. Science 190:1004-1006. Begleiter, H., Porjesz, B., and Chou, C.L. (1981). Auditory brainstem potentials in chronic alcoholics. Science 211:1064-1066. Begleiter, H., Porjesz, B., Bihari, B., and Kissin, B. (1984). Event-related potentials in boys at risk for alcoholism. Science 225:1493-1496.
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The heritability of addictive disorders h2 + range Hallucinogens (4570) Stimulants (2212) Cannabis (7659) Sedatives (4758) Gambling (3359) Smoking (10620) Alcohol (9897) Caffeine (6997) Cocaine (2206) Opiates (3494) Nature Genetics Reviews, 2005
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Frontal cortical function/behavioral inhibition Drug metabolism and response/tolerance Reward Anxiety-dysphoria/stress response Obsession/Craving Electrophysiology Imaging: brain structure and function Neuropsychology Metabolomics Gene expression Alcoholism and other addictions: The intermediate phenotypes
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Gene, stress, & substances in dyscontrol MAOA rare & common alleles: GxE, fMRI COMT Val158Met: Roles in cognition & resiliency HTTLPR: GxE for depression and suicidality
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Genes with alleles proven to modulate human behavior MAOA Brunner Syndrome HTT OCD HPRT Lesch-Nyhan Syndrome ERBA ADHD MAOA* Dyscontrol HTT* Anxiety, OCD COMT Cognition, anxiety BDNF Episodic memory ALDH2 Alcoholism ADH1B Alcoholism Rare Probablistic Deterministic Common *Regulatory
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Odds ratio 2 1 3 4 Disease Intermediate phenotype CAD Crohn For risk genes, odds ratios are larger for Intermediate Phenotypes than for Diseases (Wellcome Trust medians) BP RA T1D T2D Median of 24 disease loci 5 6 WCST/ COMT HTTLPR/ Amygdala fMRI HTTLPR/ HA MAOA/ Amygdala fMRI MAOA/ Orbitofrontal fMRI MAOA/ Hippo fMRI
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Brunner et al., Science, 1993 Brunner syndrome: X-linked dyscontrol due to the MAOA C936T stop-codon Borderline mental retardation Dyscontrol behaviors: Aggressive outbursts Arson Attempted rape Exhibitionism C C C C C C C C C C C C C C C C T T T T T T T No fibroblast MAOA activity Abnormal monoamine metabolism: ↓ urinary HIAA, HVA, VMA ↑ urinary normetanephrine & tyramine T Unaffected
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Expanding the stress connection to behavioral dyscontrol: Predisposition, early exposure, and substance abuse
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Child sexual abuse and psychiatric disorders in females ASPD 2.9 [1.4-6.0] Alcoholism [Abuse +Dep] 2.1 [1.2-3.6] Substance abuse 4.2 [2.2-7.8] Affective disorder 2.3 [1.3-4.0] Anxiety disorder 1.8 [1.0-3.1] PTSD 5.3 [2.2-12.7] Robin et al, Amer J. Psychiatry, 1997
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Addictions: A cause and effect of stress/trauma and dyscontrol Key factor in accidents, violence and sexual trauma A consequence of trauma Consequences of underage drinking A cause of allostatic changes Genes mediate liability
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* HA (±SE) Finns (433) COGA (511) Plains Indian (350) Bethesda (148) Controls AD, ASPD - AD, ASPD + Alcoholics Tend to Be Anxious * * * Ducci et al, 2007
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G. Koob, B. McEwen Allostasis and Addiction
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Sabol et al, Hum Genet, 1998 vector 3 3.5 4 5 vector 3 3.5 4 5 vector 3 3.5 4 5 A functional promoter polymorphism (MAOA-LPR) predicts MAOA expression Repeats 3 3.5 4 5 ACCGGCACCGGCACCAGTACCCGCACCAGT MAOA promoter MAOA
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Caspi et al. Science., 2002 GxE interaction of MAOA-LPR and childhood maltreatment on antisocial behavior, in males Composite index of antisocial behavior (z scores) Childhood maltreatment
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Childhood Sexual Abuse No Yes 3/3 4/4 3/3 3/4 4/4 Population fraction 0.00 0.20 0.40 0.60 0.80 1.00 ASPD + AUD AUD, no ASPD Unaffected Ducci et al, Molecular Psychiatry, 2007 3/4 GxE interaction of MAOA-LPR & childhood sexual abuse for ASPD & alcoholism Repeats 3 3.5 4 5 ACCGGCACCGGCACCAGTACCCGCACCAGT MAOA promoter MAOA
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0 5 10 15 20 25 30 35 100 200 300 400 500 600 Testosterone (pg/mL) ba (SE) = 3.49 (1.01); p=0.001 Brown/Goodwin Lifetime Aggression ASPD + AUD AUD, no ASPD no AUD, no ASPD ba (SE) = -0.94 (1.04); p=0.37 High activity MAOA-LPR 0 5 10 15 20 25 30 35 100 200 300 400 500 600 Non-additive interaction of MAOA-LPR and testosterone predicts antisocial behavior Sjoberg et al., Neuropsychopharmacology 2007 Low activity MAOA-LPR
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Andreas Meyer-Lindenberg (2006) PNAS 103, 6269-6274 MAOA-LPR predicts differential fMRI activations to angry and fearful faces in limbic and paralimbic regions (n = 142) L Amygdala Orbitofrontal Cortex Subgenual Cingulate Supragenual Cingulate
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MAOA-LPR predicts fMRI limbic activations during retrieval of aversive memories (n = 90) Andreas Meyer-Lindenberg (2006) PNAS 103, 6269-6274 L Amygdala L Hippocampus
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rhMAOA-LPR
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COMT Val158Met: Apparent counterbalancing effects in cognition and stress/anxiety Warrior Worrior
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WCST Perseverative Errors (t-scores) 30 35 40 45 50 55 60 Val/Val Val/Met Met/Met Siblings Patients Controls N = 449 F = 6.00 p = .003 COMT Val158Met and WCST 55 219 175 Egan et al, PNAS, 2001
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Fear of Uncertainty (HA2) and COMT Val158Met in females from two populations Enoch et al, Psychiatric Genetics, 2003 (HA2) Val/Val Val/Met Met/Met 4 5 6 Plains Indian [N = 148, F=3.5, p=0.03, 2 df] U.S. Caucasian [N = 75, F=3.5, p=0.09, 2 df]
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[11C]-Carfentanil binding in brain amygdala globus pallidus, n. accumbens thalamus cingulate Source:Jon-Kar Zubieta
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COMT Met158Val and µ-opioid system activation in response to sustained pain Zubieta et al, Science, 2003
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HTT 1200 nt S allele L allele HTT 14 repeats 16 repeats AP2 A>G Hu et al, AJHG, 2006 HTTLPR: Still psychiatric genetics’ most popular locus
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GxE: Interaction of HTTLPR and stress in depression Caspi et al, Science 2003
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Gene x Environment (HTT x Childhood stress) predicts suicide attempts in abstinent, African American, Substance Dependent patients (N=306) CTQ Emotional Neglect CTQ Physical Abuse Probability of Suicide Attempt Roy et al, In press HTT genotypes Low expressing High expressing
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Anxiety, Resiliency Functional Allele to Complex Behavior Alcoholism Environmental Factors OCD Marker phenotype HTT HTTLPR COMT Val158Met Executive Cognition BDNF Val66Met Episodic Memory Schizophrenia Trauma MAOA GCH1 GABRA2 Pain
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Thanks! Mary-Anne Enoch Zhifeng Zhou Ke Xu Xianzhang Hu Francesca Ducci Robert Lipsky Peihong Shen Qiaoping Yuan Colin Hodgkinson Rob Robin Bernard Albaugh Alec Roy Ahmad Hariri Deborah Mash Rajita Sinha Jon-Kar Zubieta Mary Heitzig David Scott
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ppt slide no 32 content not found
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Polygenicity: Multiple genetic variants confer risk in combination. Heterogeneity: Multiple genetic variants confer risk in different individuals. Genetic Complexity
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Genetic complexity in affected populations Polygenicity Heterogeneity
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Genetic complexity and twin concordance Polygenicity Heterogeneity DZ MZ MZ DZ Affected Unaffected
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MZ/DZ Lack of evidence for polygenic inheritance of addictions Cocaine Sedatives Stimulants Caffeine Hallucinogens Opiates Gambling Smoking Cannabis Alcohol 2 Nature Genetics Reviews, 2005 Concordance Ratios
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Pain/Stress Challenge: Hypertonic saline infusion to masseter muscle NaCl infusion rate Pain Muscle NaCl
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COMT yin/yang haplotypes in five populations & Linkage to Opioid addiction & Alcoholism Chinese African American German Caucasian Finnish Caucasian Plains Indian 0.25 0.24 0.09 0.08 0.24 0.28 0.15 0.27 0.09 0.22 M V .02 .03 .003 Case/Control 477/361 167/294 490/192 p value 178/283 175/175 <.001
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COMT Val158Met and Addiction Polysubstance abuse: Val158 Vandenburgh, Uhl and colleagues Late onset alcoholism: Met158 [Hallikainen et al, 2000] 62 early onset, 132 late onset, 267 controls. Odds ratio of 3 for late onset, p=0.017 [Tiihonen et al, 1999] 67 & 56 late onset, 3140 blood donors, 267 matched controls. Met/Met vs Val/Val Odds ratio 2.5, p =0.006, Attributable risk for Met/Met vs Val/Val 13.3%
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COMT Val158Met Val158 Met158 High anxiety, Stress reactive Alcoholism and other substance abuses Behavioral Dyscontrol
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Val158/Met158 Val/Val Val/Met Met/Met G/G C/G C/C rs4818 Mean z-score (± se) -6 -4 -2 0 2 4 6 G/G A/G A/A rs6269 ANOVA: p=0.18 p<0.01 p<0.01 Replication of COMT in experimental pain in 202 females prospectively followed for TMJ (Diatchenko et al, Hum Mol Genetics, 2005) -6 -4 -2 0 2 4 6
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GABAA Cluster ADH Cluster Long et al, 1998
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GABRA2 LD and Alcoholism Linkages Kranzler et al Edenberg et al Enoch et al * * * * * * * * * Same alleles, Same haplotype Haplotype Tagging 1121121 2212212 2212211
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Addictions Array for 130 Candidate Genes 1536 SNPs Tagging of haplotypes > 0.6% in frequency Avg of >11 SNPs/gene, Range 4 - 35 186 “perfect” genomic control SNPs (AIMs) Balanced set with cross-population D>0.7, and >10x $ <0.05/genotype 25,000 individuals genotyped (Yale, Rockefeller, Wash U, Columbia [2], Univ. Colorado, Emory, VCU, NICHD)
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ALDH1A ALDH2 CAT CYP2E1 ADH1A ADH1B ADH1C ADH4 ADH5 ADH6 ADH7 Metabolic DDC DRD1 DRD2 DRD3 DRD4 DRD5 SLC18A2 TH COMT Dopamine Serotonin HTR1A HTR1B HTR2A HTR2C HTR3A HTR3B MAOA MAOB SLC6A3 SLC6A4 TPH2 GABA CNR1 FAAH CHRM1 CHRM2 CHRM3 CHRM4 CHRM5 CHRNA4 CHRNB2 CRH CRHBP CRHR1 CRHR2 GAL NPY NPY1R NPY2R NPY5R ADCY7 AVPR1A AVPR1B CDK5R1 CREB1 CSNK1E FEV FOS FOSL1 FOSL2 GSK3B JUN MAPK1 MAPK3 MPDZ NGFB NTRK2 NTSR1 NTSR2 PPP1R1 BPRKCE BDNF CCK CCKAR CCKBR CLOCK HCRT OXT NR3C1 SLC29A1 TAC1 CART GABRA2 GABRA4 GABRA6 GABRB1 GABRB2 GABRB3 GABRD GABRG2 GABRG3 SLC6A11 SLCSA13 GAD1 GAD2 VIAAT DBI OPRM1 OPRD1 OPRK1 OPRL1 PDYN PENK PNOC POMC GLRA1 GLRA2 GLRB GPHN GRIK1 GRIN1 GRIN2A GRIN2B GRM1 ADRA1A ADRA2A ADRA2B ADRA2C ADRB2 ARRB2 SLC6A2 DBH Opioid Glycine NMDA Cannabinoid Signal Transduction Adrenergic HPA & Stress Cholinergic Other Addictions Array 130 Genes Tagged with 1350 SNPs
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Finns Plains Indians Han Chinese African American 0.98 0.01 0.01 0.00 0.05 0.92 0.02 0.00 0.01 0.01 0.98 0.00 0.11 0.02 0.02 0.85 Assignment of ancestry with 186 Ancestry-informative SNPs (Structure2, Four-factor solution)
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Ethnic factor scores of 1051 individuals in 52 CEPH populations with 186 AIMs 7-factor solution, Structure 2 Africa Middle East Asia Oceania Europe America Hodgkinson et al, unpublished
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Human Macaque Repeats in the 5 Kb region upstream of 5-HTT in Macaca mulatta and Homo sapiens 20-22 bp Imperfect repeats Sequence Identity
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Peer- reared Mother- reared Alcohol preference ls ls ll ll Biol Psych 55: 733, 2004 Arch Gen Psych 61: 1146, 2004 rh-HTTLPR has GxE effects on alcohol preference & stress response
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Serotonin Transporter Genetic Variation and the Response of the Human Amygdala Science 2002 July 19; 297(5580):400-3 Ahmad R. Hariri,1 Venkata S. Mattay,1 Alessandro Tessitore,1 Bhaskar Kolachana,1 Francesco Fera,1 David Goldman,2 Michael F. Egan,1 Daniel R. Weinberger1* 1 Clinical Brain Disorders Branch, NIMH, NIH. 2 Laboratory of Neurogenetics, NIAAA, NIH.
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LL Sx
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A common, functional NPY haplotype influencing anxiety and stress response (Zhifeng Zhou et al, submitted) The common haplotype predicts reduced brain and lymphoblast mRNA levels and plasma NPY The reduction of function haplotype predicts: Trait anxiety Reduced amygdala emotional fMRI activation Reduced amygdala pain/stress induced opioid release A functional promoter locus was identified via in vitro reporter constructs
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A functional human GCH1 haplotype predicts post-diskectomy clinical pain and experimental pain 547 normal controls 162 post-diskectomy patients Tegeder et al, Nature Medicine, 2006
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Pain-enhanced GCH1 expression in the Dorsal Root Ganglion Tegeder et al, Nature Medicine, 2006 GCH1 mRNA and protein in rat DRG are upregulated by nerve injury
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Tegeder et al, Nature Medicine, 2006 Biopterin synthesis in rat DRG is upregulated by nerve injury and blocked by a GCH1 inhibitor
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Rapid inhibition of pain and DRG neuronal activation by the GTP cyclohydrolase inhibitor, 2,4-diamino-6-hydroxypyrimidine (DAHP) Tegeder et al, Nature Medicine, 2006
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Genotype-predicted NPY expression predicts pain/stress induced opioid activation Zhou et al, submitted
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T Value Amygdala Hippocampus NPY Diplotype LL LH Activation (Arbitrary Units) (n = 11) (n = 42) P = 0.003 LL HH fMRI (n = 18) P = 0.003 P = 0.006 Genotype-predicted NPY expression predicts emotion-induced fMRI activation Zhou et al, submitted
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Genotype-predicted NPY expression predicts anxiety Zhou et al, submitted
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Anxiety, Resiliency Functional Allele to Complex Behavior Alcoholism Environmental Factors OCD Marker phenotype HTT HTTLPR COMT Val158Met Executive Cognition BDNF Val66Met Episodic Memory Schizophrenia Trauma NPY GCH1 GABRA2 Pain
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HTTLPR and anxiety [Sen, Burmeister and Ghosh, 2004] 26 Studies, 5,629 subjects p = 0.087 Substantial effect of inventory and inter-study heterogeneity p < 0.000016, NEO, corrected for heterogeneity 0.1 SD increment in TPQ Harm avoidance or NEO Neuroticism per ”s” allele
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Triallelic Functionality at HTTLPR S and LG are equivalent in expression in lymphoblasts and raphe-derived neurons AP2 transcription factor binds to LG and acts as a repressor of transcription Gel-shift and supershift assays Allele-specific, AP2-specific decoy DNA eliminates the LA:LG difference Hu et al, AJHG, 2006
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Ile425Val HTT Ozaki et al, Mol Psych, 2003
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Replication of HTTLPR-OCD linkage in Parent/child trios Collaboration with James Kennedy, Clarke Centre, Toronto Triallelic Transmitted Untransmitted S LA LG 11 27 48 16 44 26 p = 0.023 Low/High S, LG LA 20 20 41 41 p = 0.010 Hu et al, AJHG, 2006
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SS SLA SLG LALA LALG LGLG S LA LG OCD 0.21 0.34 0.03 0.34 0.07 0.01 0.38 0.56 0.06 Control 0.16 0.47 0.08 0.19 0.08 0.02 0.44 0.47 0.10 c 2 = 19.4 c 2 = 6.6 p = 0.001 p = 0.036 SS SL LL S L OCD 0.21 0.37 0.42 0.39 0.61 Control 0.16 0.55 0.29 0.44 0.56 c 2 = 15.0 c2 = 1.5 p = 0.001 p = 0.216 HTTLPR genotype and allele frequencies in 169 OCD patients and 253 controls Genotypes Alleles
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Testosterone (pg/mL) ba (SE) = 3.49 (1.01); p=0.001 Brown/Goodwin Lifetime Aggression ASPD + AUD AUD, no ASPD no AUD, no ASPD ba (SE) = -0.94 (1.04); p=0.37 High activity MAOA-LPR 0 5 10 15 20 25 30 35 100 200 300 400 500 600 Non-additive interaction of MAOA-LPR and testosterone predicts antisocial behavior Sjoberg et al., Neuropsychopharmacology 2007 Low activity MAOA-LPR