This document summarizes genetic research on obsessive-compulsive disorder (OCD). It discusses the heritability of OCD and reviews linkage and genome-wide association studies that have implicated several genes and chromosomal regions. Family and twin studies show OCD has a genetic component, with heritability estimated around 40-60%. Genome-wide linkage analysis identified chromosome 1p36 as linked to OCD. Genome-wide association studies have associated OCD with polymorphisms related to serotonin and dopamine pathways. Exome sequencing and copy number variant studies have also identified potentially relevant genes. Ongoing work includes further genome-wide studies, epigenetic analyses, and integrating multi-omic approaches to better understand the genetics of OCD.
Dr. Ángel Carracedo - Simposio Internacional 'La enfermedad de la duda: el TOC'
1. Angel Carracedo
Fundación Gallega de
Medicina Genómica-SERGAS
Universidad de Santiago de Compostela
Centro Nacional de Genotipado-ISCIII
Genética del transtorno
obsesivo-compulsivo
Fundación
Ramón Areces,
Madrid, 2013
2. The Problem of Variability
“Variability is the law of life, and
as no two faces are the same,
so no two bodies are alike,
and no two individuals react alike,
and behave alike under the
abnormal conditions which we
know as disease.”
Sir William Osler
(1849-1919)
3. TAT ACT GCG TCG GAT GCT GCG ATT GCT GAC CAA CAT CGT GAC AGT TAG ACA
AAC GAT TGA CTG TTA GGA TTG ACCA CCA ATT ACG ATG ACG TTG GAC … 3,3 x
109
4. ATT ACT GAT CGG TAG CTG AGC CAA TGG CAG
TGA TGG ATG GTA GCT GAG TGC TGG….
5. Why is genetic variation important?
variation
no variation
north
south
north
south
7. Sedentary populations, migratory populations
showed a higher proportion of long alleles for
DRD4 (p .001).
Adaptive value of long alleles of in migratory
societies and the possibility of natural selection
for a migration gene??.
DRD4— has been linked in some studies to the
personality trait of novelty-seeking and to
hyperactivity
Population Migration and the Variation of
Dopamine D4 Receptor (DRD4) Allele
Frequencies Around the Globe, Chen et al.
Evolution and Human Behavior 20: 309–324
(1999)
2,320 individuals from 39
populations
10. But still the advance in knowledge in
genes involved in complex traits is
limited !
Why is it important to find
the genes involved in OCD?
Disease stratification
Molecular classification
Target for drugs
Risk prediction Many genes
Low ORs
11. Epidemiology
• Estimated Europe prevalence 1–2% of adult population
• 75% adults often report experiencing first symptoms in childhood
•Symptoms of OCD usually begin in individuals aged 10-24 years.
• Prevalence in populations- Unknown (probably similar)
•The overall prevalence of OCD is equal in males and females,
Increased number of infections (specially stretococcal infections in
childhood
PANDAS as a subset
OCD cases after herpes infections
Evidence that serotonergic
systems modulate OCD
symptomatology.
12. OR for first degree relatives: 4-5
Concordance in MZ twins 70-90%
Hededability higher in<15y
14. % explained genetic variance
Using genetics to find genes that underlie complex traits is a potential
useful tool for a better understanding of the disease (therapeutic
targets), risk stratification, subclassification and pharmacogenetics and
pharmacogenomics
15. magnitudeofeffect
frequency of trait in the population
Linkage analysis of families
association studies in
populations
obtainable sample size
Linkage analysis or association studies ?
•linkage analysis is usually more robust in the identification of
mendelian traits
• association studies have more power to detect genes with small
effects (Risch & Merikangas, Science 1996)
16. Biological Psychiatry
Volume 72, Issue 8, 15 October 2012, Pages 629–636
Matthews et al.
Genome-Wide Linkage Analysis of Obsessive-Compulsive Disorder
Implicates Chromosome 1p36
33 Caucasian families with
≥2 childhood-onset OCD-
affected individuals from
the United States (n =
245)
The strongest result was
on chromosome
1p36.33-p36.32 (HLOD
= 3.77). At this location,
several of the families
showed haplotypes co-
segregating with OCD
17. Suicide Controls
Allele 1 Allele 2
SNP A is associated
with Phenotype
SNP A:
Allele 1 =
Allele 2 =
Human Genetic Association Study Design
19. SNP: SINGLE NUCLEOTIDE POLYMORPHISM
ATCGGCGTACCTGATTCCGAATCCGTATCG
ATCGGCGTACCTGAATCCGAATCCGTATCG
3.3 Gigabases Human Genome / >18 M SNP
1 SNP/<200 bp
1M SNPs
21. Association studies
Candidate gene approach
-Causative hypothesis or
candidate genes
Genome wide analysis (GWAs)
-No need of gene selection
-Lack of bias towards specific
genes
22.
23. SCLA1
Glutamate
transporter
9p24
Mol Psychiatry. 2012 Jun 5. doi: 10.1038/mp.2012.76. [Epub ahead of print]
Molecular genetics of obsessive-compulsive disorder: a comprehensive
meta-analysis of genetic association studies. Taylor S.
A total of 230 polymorphisms from 113 genetic association studies were
identified. A full meta-analysis was conducted for 20 polymorphisms that were
examined in 5 or more data sets, and a secondary meta-analysis (limited to the
computation of mean effect sizes) was conducted for 210 polymorphisms that
were examined in fewer than 5 data sets. In the main meta-analysis, OCD was
associated with serotonin-related polymorphisms (5-HTTLPR and HTR2A)
and, in males only, with polymorphisms involved in catecholamine modulation
(COMT and MAOA). Non significant trends were identified for two dopamine-
related polymorphisms (DAT1 and DRD3) and a glutamate-related
polymorphism (rs3087879). The secondary meta-analysis identified another 18
polymorphisms with significant ORs that merit further investigation.
26. Genome-wide association study
(GWAS) to identify low-penetrance
genes
• Require many cases and controls (but
not always)
• Can improve power by selecting cases
(early-onset, familial) and controls
(family-free)
• Search for alleles or genotypes over-
represented in cases
• Verify in other sample sets
27. Numero estimado de pacientes para el estudio de asociación conNumero estimado de pacientes para el estudio de asociación con
la enfermedadla enfermedad
NECESIDAD DE REDES-DEFINICIÓN DEL FENOTIPONECESIDAD DE REDES-DEFINICIÓN DEL FENOTIPO
29. Molecular Psychiatry , 2013 Jul;18(7):788-98.
Genome-wide association study of obsessive-
compulsive disorder
S E Stewart et al.
The International OCD Foundation Genetics
Collaborative (IOCDF-GC)
1465 cases, 5557 ancestry-matched controls and 400
complete trios remained, with a common set of 469
410 autosomal and 9657 X-chromosome single
nucleotide polymorphisms (SNPs)
30. Molecular Psychiatry advance online publication 14 August 2012.
doi:10.1038/mp.2012.85
The lowest two P-values were located within
DLGAP1 (P=2.49 × 10−6
and P=3.44 × 10−6
), a
member of the neuronal postsynaptic density
complex.
31. Genes within the imprinted
genomic region chr15q11-
13 have been reproducibly
associated with repetitive
behaviors, obsessive
compulsive behaviors, and
autism
(GWAS OCD consortium)
.
Davis et al. Partitioning the Heritability of Tourette Syndrome
and Obsessive Compulsive Disorder Reveals Differences in
Genetic Architecture- PLoS Genet Oct 2013
32. The use of the current classification schemas including DSM-IV undoubtedly
contributes to the difficulties in finding genes for psychiatric disorders. They are
based on clusters of symptoms and characteristics of clinical course that do not
necessarily describe homogenous disorders, and rather reflect common final
pathways of different pathophysiological processes
(Charney et al, 2002).
Sch 3%/75% GV
CCR 8%/35%
ADRs CCR
50%/80%
33. Common variants conferring risk of schizophrenia
Nature Stefansonn et al. Aug 2009 (SGENE Consortium)
19,000 cases and 35,000 controls from Iceland, Denmark (Aarhus), Denmark
(Copenhagen), Germany (Bonn), Germany (Munich), Hungary,
the Netherlands, Norway, Russia, Sweden, Finland;
Spain (Santiago) and Spain (Valencia)
1st
2,663 cases and 13,498 controls
2nd
top 1,500 in 4500 cases and 4500 controls
3rd
top 25 in 4,999 cases and 15,555 controls
4th
top 10 in 14,000 cases and 16,000 controls
Illumina 300 and 550 K
34. Strategies for looking missing variability in
Psychiatric Disorders
Grouping phenotypes: Phenotypes are badly defined
and overlap: Join many of them to increase numbers
Dissection of the phenotype: Endophenotypes
The use of the current classification schemas including DSM-IV undoubtedly
contributes to the difficulties in finding genes for psychiatric disorders. They are
based on clusters of symptoms and characteristics of clinical course that do not
necessarily describe homogenous disorders, and rather reflect common final
pathways of different pathophysiological processes
(Charney et al, 2002).
35. A polymorphism, located in an intron of ZNF804A, was reported to associate
with schizophrenia with a P-value of 1.61-7
, and with psychosis (schizophrenia
plus bipolar disorder) with a P-value of 1.01-8
. In this study, using 5164
schizophrenia cases and 20 709 controls, we replicated the association with
schizophrenia and, by adding bipolar disorder patients, we also confirmed the
association with psychosis
Expanding the range of ZNF804A variants conferring risk
of psychosis. Steinberg et al. Molecular Psychiatry (2010), 1–8
OCD + Depression
OCD +Tourette
OCD+ Anoexia
Common genetic background in anorexia nervosa and obs
Mas et al. J Psychiatr Res. 2013
Jun;47(6):747-54
36. CNVs:
Li et al.
A preliminary study of genotype-phenotype correlations
for rare copy number variants in children with Obsessive-Compulsive Disorder
Six CNV regions were found to be disrupting exons
in functionally relevant genes involved in neurobiological processes,
including NRXN1, SLC2A3, PRODH, CAPN14, ADRA2B2, NOTCH4 and PLXNA3.
A patient with a deletion in NRXN1, a gene previously implicated in autism
and schizophrenia, showed very early onset of severe OCD symptoms
at 4 years of age. Another patient with a deletion
in SLC2A3, a showed very low glutamatergic concentrations (and strong OCD)
Meeting ASHG 2011
42. rs12151009 7,85E-06
rs11685700 8,05E-06
rs114880897 1,80E-05
rs12327049 2,81E-05
rs114371521 2,84E-05
rs9523762 3,03E-05
rs116383774 3,22E-05
rs9903348 4,69E-05
rs198857 4,74E-05
rs7997883 9,33E-05
rs6601764 9,90E-05
376 casos, 446
controles y 37.015
marcadores (nsSNPs)
SLC6A15 (P = 2,81 x 10-5),
gen que codifica una proteína
implicada en el transporte
específico neuronal de
aminoácidos neutros que se
ha asociado previamente a
depresión mayor en un estudio
de genoma completo (Khohli
et al, Neuron 2011)
PLXNA4 (P = 3 x 10-5), gen
que codifica una proteína
implicada en la guía axonal,
cuya expresión se ha visto
disminuida en una muestra de
cerebro de pacientes con
diagnóstico de autismo (Suda
S et al, Mol Autism 2011).
Réplica Danielle Cath
800 muestras Univ. Utrecht
43. Trends Cogn Sci. 2012 Jan;16(1):81-91. Epub 2011 Dec 10.
Neurocognitive endophenotypes of impulsivity and compulsivity: towards
dimensional psychiatry.
Robbins TW, Gillan CM, Smith DG, de Wit S, Ersche KD.
45. Various animal models have confirmed the importance of the 5-HT,
and dopamine systems in the neurobiology and treatment of OCD
46. DNA methylation is a major epigenetic
modification with direct implications in gene
expression patterns
DNA methylation occurs at the cytosine bases in
CG dinucleotides, which are often located in
enriched regions called CpG islands. When CpG
islands become methylated, the promoter
becomes stably silent
New challenges: Methylation
.
47. DEEP OMIC APPROACHES
DNA SEQUENCING AND METHYLATION
RNA SEQ (SMALL AND LONG)
METABOLITES
MICROBIOME
INTEGRATIVE BIOLOGY APPROACHES
EXPLORE
G x E
INTERACTIONS
Genomics
Micro RNA
Transcriptomics
Epigenomics
48. Expert Opin Drug Discov. 2013 Oct 23.
[Glutamate drugs and pharmacogenetics of
OCD: a pathway-based exploratory approach.
Expert opinion: In the genetically informed
network, known genes and identified key
connecting components, including DLG4 (a
developmental gene), PSD-95 (a synaptic
scaffolding protein) and PSEN1 (presenilin, a
regulator of secretase), conform a group of
potential pharmacological targets.
49. Pino Alonso – Hospital de Bellvitge
Xavier Estivill-CRG
Noa Carrera-JavierCostas
Editor's Notes
NOTES FOR PRESENTERS:
According to some studies, OCD is the fourth most common mental disorder after depression, alcohol and substance misuse, and social phobia. It has a lifetime prevalence in community surveys of about 2–3%. However, the instruments used have been criticised and may have over-diagnosed OCD, so the true prevalence may be somewhat lower.
There is remarkable consistency in the lifetime and annual prevalence of OCD from studies conducted across the world. The mean age of onset is in late adolescence for men and early twenties for women, although onset may occur in a wide range of ages.
However, it may take individuals between 10–15 years or longer to seek professional help. There is often comorbidity with a range of disorders, especially depression, anxiety, alcohol or substance misuse, BDD, or an eating disorder.