# Presentation: 548462

## Functional alleles & intermediate phenotypes in alcoholism and dyscontrol disorders

- David Goldman
- davidgoldman@mail.nih.gov

## 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.

## 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*

## 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

- 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

## 
Gene, stress, & substances in dyscontrol

MAOA rare & common alleles: GxE, fMRI
COMT Val158Met: Roles in cognition & resiliency
HTTLPR: GxE for depression and suicidality

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

## 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*

## 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

## Brunner syndrome: X-linked dyscontrol due to the MAOA C936T stop-codon

*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

## Expanding the stress connection to behavioral dyscontrol: Predisposition, early exposure, and substance abuse

## 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

## 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

## Alcoholics Tend to Be Anxious

- *

- HA
- (±SE)

- Finns
- (433)

- COGA (511)

- Plains Indian
- (350)

- Bethesda
- (148)

- Controls

- AD,  ASPD -

- AD,  ASPD +

- *

- *

- *

*Ducci et al, 2007*

## Allostasis and Addiction

- G. Koob, B. McEwen

## A functional promoter polymorphism (MAOA-LPR) predicts MAOA expression

- 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*

## GxE interaction of MAOA-LPR and childhood maltreatment on antisocial behavior,  in males

*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

## 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*

## Non-additive interaction of MAOA-LPR and testosterone predicts antisocial behavior 

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- 100

- 200

- 300

- 400

- 500

- 600

- Testosterone (pg/mL)

- aSEp

- Brown/Goodwin
- Lifetime Aggression

- ASPD + AUD

- AUD, no ASPD

- no AUD, no ASPD

- aSEp

- 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*

## MAOA-LPR predicts differential fMRI activations to angry and fearful faces in limbic and paralimbic regions (n = 142) 

- 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

## 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

## rhMAOA-LPR

*rhMAOA-LPR*

## COMT Val158Met: Apparent counterbalancing effects in cognition and stress/anxiety

- Warrior

- Worrior

## COMT Val158Met and WCST 

**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

## 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*]

## [11C]-Carfentanil binding in brain

- [11C]-Carfentanil binding in brain

- amygdala

- globus pallidus,
-  n. accumbens

- thalamus

- cingulate

- Source:Jon-Kar Zubieta

## COMT Met158Val and μ-opioid system activation in response to sustained pain

*COMT* *Met158Val* and μ-opioid system activation in response to sustained pain

*Zubieta et al, Science, 2003*

## HTTLPR: Still psychiatric genetics’

*HTT*

- 1200 nt

- S allele

- L allele

*HTT*

- 14 repeats

- 16 repeats

- AP2

- A>G

- Hu et al,  AJHG, 2006

- most popular locus

- GxE: Interaction of HTTLPR and stress in depression

- Caspi et al, Science 2003

## Gene x Environment  (HTT x Childhood stress) 

- 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***

## Functional Allele to Complex Behavior

- Anxiety,
- Resiliency

- Alcoholism

- Environmental
- Factors

- OCD

- Marker phenotype

*HTT*
- HTTLPR

*COMT*
- Val158Met

- Executive
- Cognition

*BDNF*
- Val66Met

- Episodic
- Memory

- Schizophrenia

- Trauma

*MAOA*

*GCH1*

*GABRA2*

- Pain

## 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

## Polygenicity: Multiple genetic variants confer risk in combination.

- Heterogeneity: Multiple genetic variants confer risk in different individuals.

- Genetic Complexity

## Genetic complexity in affected populations

- Polygenicity

- Heterogeneity

## Genetic complexity and twin concordance

- Polygenicity

- Heterogeneity

*DZ*

*MZ*

*MZ*

*DZ*

- Affected

- Unaffected

## Lack of evidence for polygenic inheritance of addictions

- MZ/DZ

- Cocaine

- Sedatives

- Stimulants

- Caffeine

- Hallucinogens

- Opiates

- Gambling

- Smoking

- Cannabis

- Alcohol

- 2

*Nature Genetics Reviews, 2005*

- Concordance Ratios

## Pain/Stress Challenge: 

- Pain/Stress Challenge:
- Hypertonic saline infusion to masseter muscle

- NaCl infusion rate

- Pain

- Muscle

- NaCl

## 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*

## 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%

## COMT Val158Met

- Val158

- Met158

*High anxiety,*
*Stress reactive*

- Alcoholism and
- other substance abuses

*Behavioral*
*Dyscontrol*

## Replication of COMT in experimental pain in 202 females prospectively followed for TMJ (Diatchenko et al, Hum Mol Genetics, 2005)

- Val158/Met158

**Val/Val**

**Val/Met**

**Met/Met**

**G/G**

**C/G**

**C/C**

- rs4818

- Mean z-score (± se**)**

**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)

## Long et al, 1998

- GABAA Cluster

- ADH Cluster

*Long et al, 1998*

## GABRA2 LD and Alcoholism Linkages

*Kranzler et al*

*Edenberg et al*

*Enoch et al*

***

***

***

***

***

***

***

***

***

*Same alleles,*
*Same haplotype*

*Haplotype*
*Tagging*

*1121121*

*2212212*

*2212211*

## 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 >0.7, and >10x
- $ <0.05/genotype
- 25,000 individuals genotyped (Yale, Rockefeller, Wash U, Columbia [2], Univ. Colorado, Emory, VCU, NICHD)

## Addictions Array 

- 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***

## 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)*

## Ethnic factor scores of 1051 individuals in 52 CEPH populations 

- 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

## Repeats in the 5 Kb region upstream of 5-HTT in 

- 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*

## Peer-

*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

## Serotonin Transporter Genetic Variation and the Response of the 

**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. Weinberger****1***** **
- 1 Clinical Brain Disorders Branch, NIMH, NIH.2 Laboratory of Neurogenetics, NIAAA, NIH.

|    |
| --- |
| Nature Neuroscience  8, 828 - 834 (2005) 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression
Lukas Pezawas, Andreas Meyer-Lindenberg, Emily M Drabant, Beth A Verchinski, Karen E Munoz, Bhaskar S Kolachana, Michael F Egan, Venkata S Mattay, Ahmad R Hariri & Daniel R Weinberger |
|   |
|  |
|  |

|                                                                                                                                                                                        |
| --- |

| Statistical functional connectivity maps between bilateral 
amygdala and perigenual anterior cingulate cortex |
| --- |

- LL

- Sx

## 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

## A functional human GCH1 haplotype predicts 

- 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*

## 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*

## Biopterin synthesis in rat DRG

*Tegeder et al, Nature Medicine, 2006*

*Biopterin synthesis in rat DRG*
*is upregulated by nerve injury and blocked by a GCH1 inhibitor*

## Rapid inhibition of pain and DRG neuronal activation 

- 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*

## Genotype-predicted NPY expression predicts pain/stress 

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

## Genotype-predicted NPY expression predicts 

- 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*

## Genotype-predicted NPY expression predicts anxiety

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

## Functional Allele to Complex Behavior

- Anxiety,
- Resiliency

- Alcoholism

- Environmental
- Factors

- OCD

- Marker phenotype

*HTT*
- HTTLPR

*COMT*
- Val158Met

- Executive
- Cognition

*BDNF*
- Val66Met

- Episodic
- Memory

- Schizophrenia

- Trauma

*NPY*

*GCH1*

*GABRA2*

- Pain

## 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

## 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

## Ile425Val

- HTT

- Ozaki et al, Mol Psych, 2003

## 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

## HTTLPR genotype and allele frequencies in 169 OCD patients and 253 controls

- 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
- 		           2* = *19.4                 		         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
- 		            2* =  *15.0* *			           2 = 1.5
- 		             p = 0.001			           p = 0.216

-                            Genotypes           		    Alleles

## Non-additive interaction of MAOA-LPR and testosterone predicts antisocial behavior 

- Testosterone (pg/mL)

- aSEp

- Brown/Goodwin
- Lifetime Aggression

- ASPD + AUD

- AUD, no ASPD

- no AUD, no ASPD

- aSEp

- 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*