Download Free Medical Functional alleles and intermediate phenotypes in alcoholism and dyscontrol disorders PowerPoint Presentation

Functional alleles and intermediate phenotypes in alcoholism and dyscontrol disorders PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Check out this medical presentation on Neurology, which is titled "Functional alleles & intermediate phenotypes in alcoholism and dyscontrol disorders", to know about functional alleles and intermediate phenotypes in alcoholism and dyscontrol disorders.

Tags : Neurology, Functional alleles, intermediate phenotypes, alcoholism, dyscontrol disorders

Published on : Aug 18, 2021 | Views : 1724 | Downloads : 0

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Functional alleles & intermediate phenotypes in alcoholism and dyscontrol disorders David Goldman davidgoldman@mail.nih.gov
Slide 2-

1935-2006
Slide 3-

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.
Slide 4-

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
Slide 5-

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
Slide 6-

Gene, stress, & substances in dyscontrol MAOA rare & common alleles: GxE, fMRI COMT Val158Met: Roles in cognition & resiliency HTTLPR: GxE for depression and suicidality
Slide 7-

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
Slide 8-

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
Slide 9-

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
Slide 10-

Expanding the stress connection to behavioral dyscontrol: Predisposition, early exposure, and substance abuse
Slide 11-

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
Slide 12-

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
Slide 13-

* 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
Slide 14-

G. Koob, B. McEwen Allostasis and Addiction
Slide 15-

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
Slide 16-

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
Slide 17-

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
Slide 18-

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
Slide 19-

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
Slide 20-

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
Slide 21-

rhMAOA-LPR
Slide 22-

COMT Val158Met: Apparent counterbalancing effects in cognition and stress/anxiety Warrior Worrior
Slide 23-

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
Slide 24-

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]
Slide 25-

[11C]-Carfentanil binding in brain amygdala globus pallidus, n. accumbens thalamus cingulate Source:Jon-Kar Zubieta
Slide 26-

COMT Met158Val and µ-opioid system activation in response to sustained pain Zubieta et al, Science, 2003
Slide 27-

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
Slide 28-

GxE: Interaction of HTTLPR and stress in depression Caspi et al, Science 2003
Slide 29-

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
Slide 30-

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
Slide 31-

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
Slide 32-

ppt slide no 32 content not found
Slide 33-

Polygenicity: Multiple genetic variants confer risk in combination. Heterogeneity: Multiple genetic variants confer risk in different individuals. Genetic Complexity
Slide 34-

Genetic complexity in affected populations Polygenicity Heterogeneity
Slide 35-

Genetic complexity and twin concordance Polygenicity Heterogeneity DZ MZ MZ DZ Affected Unaffected
Slide 36-

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
Slide 37-

Pain/Stress Challenge: Hypertonic saline infusion to masseter muscle NaCl infusion rate Pain Muscle NaCl
Slide 38-

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
Slide 39-

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%
Slide 40-

COMT Val158Met Val158 Met158 High anxiety, Stress reactive Alcoholism and other substance abuses Behavioral Dyscontrol
Slide 41-

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
Slide 42-

GABAA Cluster ADH Cluster Long et al, 1998
Slide 43-

GABRA2 LD and Alcoholism Linkages Kranzler et al Edenberg et al Enoch et al * * * * * * * * * Same alleles, Same haplotype Haplotype Tagging 1121121 2212212 2212211
Slide 44-

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)
Slide 45-

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
Slide 46-

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)
Slide 47-

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
Slide 48-

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
Slide 49-

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
Slide 50-

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.
Slide 51-

LL Sx
Slide 52-

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
Slide 53-

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
Slide 54-

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
Slide 55-

Tegeder et al, Nature Medicine, 2006 Biopterin synthesis in rat DRG is upregulated by nerve injury and blocked by a GCH1 inhibitor
Slide 56-

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
Slide 57-

Genotype-predicted NPY expression predicts pain/stress induced opioid activation Zhou et al, submitted
Slide 58-

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
Slide 59-

Genotype-predicted NPY expression predicts anxiety Zhou et al, submitted
Slide 60-

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
Slide 61-

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
Slide 62-

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
Slide 63-

Ile425Val HTT Ozaki et al, Mol Psych, 2003
Slide 64-

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
Slide 65-

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
Slide 66-

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