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GENETICS OF SUDs
AND
NEURODEVELOPMENTAL DISORDERS
J. Antoni Ramos-Quiroga MD, PhD
Department of Psychiatry. CIBERSAM
Hospi...
Financial disclosures
Company Speaker Consultant Grants
Janssen-Cilag X X X
Lilly X X X
Shire X X X
Novartis X
Laboratorio...
ADHD across the life span
Behavioural problems
Pre-school
School age
Adolescence
Adult
Behavioural problems
Academic probl...
DUAL DISORDERS
GENETICS OF COMORBIDITY
ADHD
Bipolar Disorder
Schizophrenia
Major Depression
Autism
h2
SNP =
28%
λSNP = 1.71
Genetic relat...
SUD & ADHD
ADHD individuals
have more riskfor
developSUD
ADHD acts as a riskfactorfor SUD
develompental
IS ADHD A GENETIC DISORDER?
Biederman et al. Lancet 2005
1. Twin Studies
Major concordance between monozygotic twins than ...
IS ADHD A GENETIC DISORDER?
1. Twin Studies
Major concordance between monozygotic twins than dizygotic twins;
HEREDABILITY...
IS ADHD A GENETIC DISORDER?
1. Twin Studies
Major concordance between monozygotic twins than dizygotic twins;
HEREDABILITY...
Children ADHD (cADHD)
30-50%
Adults ADHD (aTDAH)
 Major risk of ADHD:
• Offspring's aADHD than familiars of cADHD.
• In f...
GWAS:… EUREKA!!!!!
10 loci
8 look robust
On the path!
New ADHD meta-analysis
18.284 cases 33.836
Gen 1
Mutations in a causal gen
Gen 1
Gen 3Gen 2
Gen 1
Gen 3
Gen 2 COMPLEX DISORDER
Predisposition Gens
Environmental Fact...
Environment
factors
Genetic
facto
rs
GENETIC
RISK
FACTOR
S
PROTECTOR
GENETIC
FACTORS
ENVIRONMENT
RISK
FACTORS
PROTECTOR
EN...
ADHD-SUD-ADHD
COMMON GENETIC RISKS FACTORS
Goldman et al. 2005
 Severity
 Withdraw
al
 Relapse
COMMON GENETIC RISKS FACTORS
ADHD
ADDICTION
Common susceptibility
genetic factors
Goldman et al. 2005
 Severity
 Withdraw
al
 Relapse
COMMON GENETIC...
COMMON RISK FACTORS SUD&ADHD
Serotoninergic SystemNoradrenergic System
Dopaminergic
System
Endocannabioid SystemNeurotrophic factorsOpioid System
CDH13 AND ADHD
AlcoholNicotine
Methanphetamine
5HT2A
COMMON RISK FACTORS SUD&ADHD
Serotoninergic
System
Noradrenergic System
Dopaminergic
System
Endocannabioid
System
Neurotro...
SNARE in ADHD
Coloboma mouse
• Spontaneous locomotor
hyperactivity
• Reduction in dopamine release in
dorsal striatum (bra...
SNARE in ADHD
Coloboma mouse
• Spontaneous locomotor
hyperactivity
• Reduction in dopamine release in
dorsal striatum (bra...
• 144 SNPs in 6 candidate
Case-controlassociationstudy
360 SUD vs 360
controls
506 AdultADHD (60% No SUD y 40% SUD) vs 905...
• 144 SNPs in 16 candidate
Case-controlassociationstudy
360 SUD vs 360
controls
506 AdultADHD (60% No SUD y 40% SUD) vs 90...
RM
1
Munc13
-1
Rab
3
Munc 18-
1
TRANSPORT AND FIXING
IN THE MEMBRANE
SNAP-STX1 VAMP-
FUSION
NSF
α-SNAP
RECYCLE
SYT
CPL
X
E...
SNARE (solubleN-ethylmaleimide-sensitivefactor(NSF) attachmentproteinreceptor)
-log(p-value)
Bonferroni
p= 3e-5
FDR
p=
0.00
51
p=0.05
NSF
SNARE and SUD
NSF
rs183211-rs17698176 P-value;OR (CI)
A-T 0.017; 0.77 (0.61-0.95)
G-T 0.013; 1.3 (1.06-1.60)
10kb
rs18321
1rs17692129
rs...
Time between initial consumption and dependence onset (years)
Numberofpatients
G-T haplotype
carrierG-T haplotype non-carr...
10kb
rs183211
rs17692129
rs7224296
rs17698176
Departure from HWE in control
group
NSF and ADHD
NSF
Bonferroni
p=7e-5
FDR
p=4.5e-
3
p=0.05
-log(p-
value)
rs941298 rs2293485 rs3793243 rs4363087
STX1A
SNARE and ADHD
1Kb
STX1A
rs941298-rs2293485-
rs4363087
TDAH total
p-valor; OR (CI)
TDAH Combinado
p-valor; OR (CI)
TDAH Inatento
p-valor;...
The association between NSF gene and SUD or STX1A with
ADHD suggests the existence of a distinct genetic factors that aff...
STX1A
SERT
DAT
NET
STX1A regulates the DAT-mediated amphetamine-induced efflux, which
suggests that altered STX1A function...
This finding also points to the assessment of the ADHD or SUD
comorbidity as an alternative approach to identify distinct...
SNARE COMPLEX AND SUD
SNARE COMPLEX AND ADHD
ACKNOWLEDGEMENTS
GENETICS OF SUDs
AND
NEURODEVELOPMENTAL DISORDERS
J. Antoni Ramos-Quiroga MD, PhD @ramosquiroga2
Department of Psychiatry....
GENETICS OF SUDs AND NEURODEVELOPMENTAL DISORDERS
GENETICS OF SUDs AND NEURODEVELOPMENTAL DISORDERS
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GENETICS OF SUDs AND NEURODEVELOPMENTAL DISORDERS

This material was presented in the 25th European Congress of Psychiatry which was organised by the European Psychiatry Association in Florence, Italy from 1-4th April 2017.
I had access to the material as I attended the full Congress.
Please note that this material remains the intellectual property of the European Psychiatry Association and its authors and any citation should include a full reference to it.
For more information on the EPA and how to become a member, please visit:
http://www.europsy.net/

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GENETICS OF SUDs AND NEURODEVELOPMENTAL DISORDERS

  1. 1. GENETICS OF SUDs AND NEURODEVELOPMENTAL DISORDERS J. Antoni Ramos-Quiroga MD, PhD Department of Psychiatry. CIBERSAM Hospital Universitari Vall d’Hebron Universitat Autònoma de Barcelona Centro de InvestigaciónBiomédica En Red de Salud Mental
  2. 2. Financial disclosures Company Speaker Consultant Grants Janssen-Cilag X X X Lilly X X X Shire X X X Novartis X Laboratorios Rubió X X X Almirall X Rovi X Ferrer X X X Lundbeck X Alicia Koplowitz Foundation X Instituto Carlos III- EU FP7-H2020 X X
  3. 3. ADHD across the life span Behavioural problems Pre-school School age Adolescence Adult Behavioural problems Academic problems Social maladaptation Poor self-esteem Academic problems Social maladaptation Poor self-esteem Legal problems Injuries Tobacco, substance use disorders Vocational problems Interpersonal relations Poor self-esteem Substance abuse AccidentsRamos-Quiroga JA, et al. Expert Rev Neurother 2014;14:553-67.
  4. 4. DUAL DISORDERS
  5. 5. GENETICS OF COMORBIDITY ADHD Bipolar Disorder Schizophrenia Major Depression Autism h2 SNP = 28% λSNP = 1.71 Genetic relationshipbetween five psychiatricdisordersestimatedfromgenome-wide SNPs
  6. 6. SUD & ADHD ADHD individuals have more riskfor developSUD ADHD acts as a riskfactorfor SUD develompental
  7. 7. IS ADHD A GENETIC DISORDER? Biederman et al. Lancet 2005 1. Twin Studies Major concordance between monozygotic twins than dizygotic twins; HEREDABILITY 76%
  8. 8. IS ADHD A GENETIC DISORDER? 1. Twin Studies Major concordance between monozygotic twins than dizygotic twins; HEREDABILITY 76% 2. Familiar studies Relative Risk of 2 to 8 to develop the disorder between familiars of ADHD subjects. Biederman et al. Biological Psychiatry 2005
  9. 9. IS ADHD A GENETIC DISORDER? 1. Twin Studies Major concordance between monozygotic twins than dizygotic twins; HEREDABILITY 76% 2. Familiar studies Relative Risk of 2 to 8 of develop the disorder between familiars of ADHD subjects. 3. Adoption studies Biological familiars of ADHD patients present more risk to develop ADHD than adoptive familiars. Biederman et al. Biological Psychiatry 2005
  10. 10. Children ADHD (cADHD) 30-50% Adults ADHD (aTDAH)  Major risk of ADHD: • Offspring's aADHD than familiars of cADHD. • In familiars of adolescents with ADHD than familiars of cADHD.  ADHD is more prevalent between familiars of aADHD than familiars of patients with non-persistent ADHD. ADULT ADHD: MAJOR GENETIC RISK
  11. 11. GWAS:… EUREKA!!!!! 10 loci 8 look robust On the path! New ADHD meta-analysis 18.284 cases 33.836
  12. 12. Gen 1 Mutations in a causal gen Gen 1 Gen 3Gen 2 Gen 1 Gen 3 Gen 2 COMPLEX DISORDER Predisposition Gens Environmental Factors Psychosocial adversiti es Nicotine Abuse during pregnant Low weight at delivery MENDELIAN ILLNESS COMPLEX AND MULTIFACTORIAL
  13. 13. Environment factors Genetic facto rs GENETIC RISK FACTOR S PROTECTOR GENETIC FACTORS ENVIRONMENT RISK FACTORS PROTECTOR ENVIRON MET FACTORS LOW RISK TO DEVELOP THE DISORDER HIGH RISK TO DEVELOP THE DISORDER COMPLEX AND MULTIFACTORIAL
  14. 14. ADHD-SUD-ADHD
  15. 15. COMMON GENETIC RISKS FACTORS
  16. 16. Goldman et al. 2005  Severity  Withdraw al  Relapse COMMON GENETIC RISKS FACTORS
  17. 17. ADHD ADDICTION Common susceptibility genetic factors Goldman et al. 2005  Severity  Withdraw al  Relapse COMMON GENETIC RISKS FACTORS
  18. 18. COMMON RISK FACTORS SUD&ADHD
  19. 19. Serotoninergic SystemNoradrenergic System Dopaminergic System Endocannabioid SystemNeurotrophic factorsOpioid System
  20. 20. CDH13 AND ADHD AlcoholNicotine Methanphetamine
  21. 21. 5HT2A
  22. 22. COMMON RISK FACTORS SUD&ADHD Serotoninergic System Noradrenergic System Dopaminergic System Endocannabioid System Neurotrophic factorsOpioid System
  23. 23. SNARE in ADHD Coloboma mouse • Spontaneous locomotor hyperactivity • Reduction in dopamine release in dorsal striatum (brain region implicated in ADHD)
  24. 24. SNARE in ADHD Coloboma mouse • Spontaneous locomotor hyperactivity • Reduction in dopamine release in dorsal striatum (brain region implicated in ADHD)
  25. 25. • 144 SNPs in 6 candidate Case-controlassociationstudy 360 SUD vs 360 controls 506 AdultADHD (60% No SUD y 40% SUD) vs 905 controls 13% Comorbidit y with ADHD
  26. 26. • 144 SNPs in 16 candidate Case-controlassociationstudy 360 SUD vs 360 controls 506 AdultADHD (60% No SUD y 40% SUD) vs 905 controls 13% Comorbidit y with ADHD 38% Comorbidit y with SUD
  27. 27. RM 1 Munc13 -1 Rab 3 Munc 18- 1 TRANSPORT AND FIXING IN THE MEMBRANE SNAP-STX1 VAMP- FUSION NSF α-SNAP RECYCLE SYT CPL X EXOCITOSIS CONTROL SNARE (solubleN-ethylmaleimide-sensitivefactor(NSF) attachmentproteinreceptor)
  28. 28. SNARE (solubleN-ethylmaleimide-sensitivefactor(NSF) attachmentproteinreceptor)
  29. 29. -log(p-value) Bonferroni p= 3e-5 FDR p= 0.00 51 p=0.05 NSF SNARE and SUD
  30. 30. NSF rs183211-rs17698176 P-value;OR (CI) A-T 0.017; 0.77 (0.61-0.95) G-T 0.013; 1.3 (1.06-1.60) 10kb rs18321 1rs17692129 rs7224296 rs17698176 NSF SNARE and SUD
  31. 31. Time between initial consumption and dependence onset (years) Numberofpatients G-T haplotype carrierG-T haplotype non-carriers OR= 3.58 (2.00-6.41), p= 2.98 e-06 NSF SNARE and SUD
  32. 32. 10kb rs183211 rs17692129 rs7224296 rs17698176 Departure from HWE in control group NSF and ADHD NSF
  33. 33. Bonferroni p=7e-5 FDR p=4.5e- 3 p=0.05 -log(p- value) rs941298 rs2293485 rs3793243 rs4363087 STX1A SNARE and ADHD
  34. 34. 1Kb STX1A rs941298-rs2293485- rs4363087 TDAH total p-valor; OR (CI) TDAH Combinado p-valor; OR (CI) TDAH Inatento p-valor; OR (CI) T-T-C 0.0041; 1.28 (1.08-1.51) 0.0089; 1.30 (1.06-1.58) - C-C-T 1.9e-0.4; 1.36 (1.16-1.58)* 0.0033; 1.31(1.09-1.59)* 0.010; 1.36 (1.08-1.75)* rs941298 rs2293485 rs3793243rs4363087 STX1A STX1A as a riskfactorfor ADHD
  35. 35. The association between NSF gene and SUD or STX1A with ADHD suggests the existence of a distinct genetic factors that affect the same pathway. NSF rs183211-rs17698176 STX1A rs941298-rs2293485-rs4363087
  36. 36. STX1A SERT DAT NET STX1A regulates the DAT-mediated amphetamine-induced efflux, which suggests that altered STX1A function may modulate the activity of neurotransmitter systems previously associated with the pathology of ADHD. NSF NSF has an essential role in the modulation of the trafficking between the plasma membrana and endosomes and in the binding of several cell-surface signalling receptors DRD1 and DRD5
  37. 37. This finding also points to the assessment of the ADHD or SUD comorbidity as an alternative approach to identify distinctive, homogeneous and consistent subgroups of ADHD that could facilitate the identification of underlying genetic factors. NSF STX1A?
  38. 38. SNARE COMPLEX AND SUD
  39. 39. SNARE COMPLEX AND ADHD
  40. 40. ACKNOWLEDGEMENTS
  41. 41. GENETICS OF SUDs AND NEURODEVELOPMENTAL DISORDERS J. Antoni Ramos-Quiroga MD, PhD @ramosquiroga2 Department of Psychiatry. CIBERSAM Hospital Universitari Vall d’Hebron Universitat Autònoma de Barcelona Centro de InvestigaciónBiomédica En Red de Salud Mental

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  • DivSandhu

    Oct. 5, 2019

This material was presented in the 25th European Congress of Psychiatry which was organised by the European Psychiatry Association in Florence, Italy from 1-4th April 2017. I had access to the material as I attended the full Congress. Please note that this material remains the intellectual property of the European Psychiatry Association and its authors and any citation should include a full reference to it. For more information on the EPA and how to become a member, please visit: http://www.europsy.net/

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