Transcript DNA and Gene Expression

Developmental Psychopathology
Chapter 12
Wide Range
• As high as 1 in 4 children with diagnosable
disorder
• Pervasive developmental, attention deficit
and disruptive behaviour, anxiety, tic,
elimination
Developmental Disorders
• Recently, lots of focus on childhood, but
technically, cover the whole lifespan
• A number of adult disorders manifest early
– Median age onset for anxiety and impulsecontrol disorders ~11 years, vs. 30 years for
mood disorders
– About half of diagnosed disorders identifiable
by age 14
Autism
• First formally documented 1943
• Neurodevelopmental disorder
– Language, social-emotional, theory of mind
disfunction, restricted, repetitive interests and
behaviours
• 1-2 in 1000 for strict diagnosis and 1 in 160
for broader diagnostic criteria (Austism
Spectrum Disorder, ASD)
Etiology
• Early-mid 20th C. thought to be due to poor
parenting (“refrigerator mothers”) and/or
brain damage (no obvious neuronal damage)
• Folstein & Rutter (1977): landmark twin
study showing genetic role
• Now recognized to be one of the most
heritable mental disorders
Autism Spectrum Disorder
• Autism
• Asperger syndrome
– Social impairment, motor clumsiness, no delay in
cognitive or language development, stereotyped and
restricted patterns of activities and interests, intense
preoccupation with a narrow subject
• Pervasive developmental disorder not otherwise
specified (PDD-NOS)
– Criteria not met for specific disorder
– Usually milder than autism
Non-ASD Conditions of Interest
• Williams
– Highly verbal and overly sociable, but lack
understanding of social cognitive situations, inhibited
intelligence
– Series of deletions in 7q11.23
• Obsessive Compulsive Disorder
– Role for genes involved in serotonin pathway
– Autistics also show repetitive, obsessive behaviours
– Serotonin pathway also implicated in some autism
studies
Male Connection
• 4:1 male-to-female ratio
• Fathers of autistics
– Better at piecemeal local processing tasks
– Weak central coherence
• Physics, engineering, etc. in male relatives
of autistics
• So-called “extreme male” brain
• Consider, folk physics vs. folk psychology
Social Cognition
autistic
• No joint attention, poor at deceit,
no/limited pretend play, poor
grasp of desire
• Similar ToM deficits in Williams
and OCD as in ASD
50
Down’s
– No IQ or specific cognitive deficits
normal
• “Theory of mind”
• Autistics fail false belief test
Passing (%)
100
Neuro
• Medial frontal cortex
– Mental state attributions, social behaviour, language
deficits, inappropriate affect
– Very similar to autistics
• Mirror neurons
– Autistic children show reduced mirror neuron activity
than normal children (Wicker, 2005)
– Normal and autistic teens imitate and identify distinct
facial expressions, but autistics don’t show mirror
neuron activity
– Autistic knows the expression cognitively, but doesn’t
empathize
Autism
• Genetics complex
• Can’t be traced to single-gene mutation or
chromosomal abnormalities
• Unclear if ASD is explained more by polygenic
effects or rare mutations with major effects
• ASD as quantitative extreme of a continuum of
normal variation
– “Abnormal is normal”
Heritability
• MZ twins show 60% concordance (3-5% in
DZ twins)
• Heritability estimate of 90%
• Relatives show traits phenotypically similar,
but milder, to autism’s diagnostic criteria
more frequently than controls
Identifying Genes: Inconsistent
Results
• Select homogeneous groups of subjects for
molecular genetic studies
– Characteristics such as language delay
– Clear history of developmental regression
• Unclear whether such characteristics are more
influenced by genetics or environment
• More power if subgroups could be chosen based
on behavioural genetic analyses identifying
characteristics with strong genetic basis
Genome Screens
• Over a dozen genome-wide linkage analysis
studies
• Suggestive linkage peaks, but relatively
little congruence across them
• Most consistent evidence for linkage on 7q
and 11p
Genome-wide Linkage Scans
•
•
Red: LOD>3; dark grey: LOD>2; light grey: LOD>1.5
Source: Losh et al. (2008)
Inconsistent Findings
• Genome-wide linkage analysis useful for
identifying highly penetrant single-gene
disorders
• Poorly suited for polygenic disorders with
multiple risk alleles of small effects
Candidate Gene Association
• 5-15% of ASD individuals have identifiable
single gene or chromosome disorders (e.g.,
Jamain et al. 2003, Durand et al. 2007)
• Molecular genetic studies
• Generally, inadequate sample sizes and
sparse genotyping
• Over 100 possible genes identified so far
• Only a few supported by replication
MET Gene
• 7q31 region
• Encodes a tyrosine kinase receptor involved
in neuronal growth and organization
• Decreased MET protein levels in autopsied
cortical tissue from autistic individuals
SLC6A4
• Role in serotonin (5HT) pathway
• Elevated levels of platelet 5HT in 25-30%
of cases of autism
• Studies of SLC6A4 locus generally support
its involvement in autism, but no
convergence on specific allele or
polymorphism to date
RELN
• Reelin encodes a protein controlling
intercellular interactions in neuronal
migration in brain development
• RELN maps to 7q22 region
• A large polymorphic trinucleotide repeat in
RELN gene has been linked to autism in
several studies
• RELN also implicated in schizophrenia and
OCD
Tumor Suppressor Genes
• PTEN involved in preventing uncontrolled
cell growth and division
– Mutations linked to Cowden syndrome and
macrocephaly, both also correlated with autism
• TSC1 and TSC2 encode growth suppressor
proteins
– Mutations cause tuberous sclerosis complex;
autism in 15-60% of cases
Structural Variants
• New technologies have led to greater
appreciation for frequency of de novo
structural variation in human genome
• Copy Number Variations (CNVs)
– Deletions and duplications of chunks of DNA
– Sort of the other end of spectrum from SNPs
• CNVs could cause subsets of cases in
complex diseases, like autism
CNVs in Autism Studies
• 24% of autistics had de novo CNVs
(Jacquemont et al., 2006)
• 593-kb deletions found in three autism
study samples in the 16p11.2 region (Weiss
et al., 2008)
• Multiple rare genic CNVs (both genomewide and at specific loci) involved in ASD
(Pinto et al. 2010)
Mouse Models
• Recently, mouse models developed that
reflect genetic alterations associated with
autism
• Some mutant lines based on monogenic
aberrations
• Others relevant to loci for autism
susceptibility identified by human linkage
or association studies
• Prenatal or neonatal environmental
challenges
Social Deficits
• Social disfunction and repetitive behaviour central
phenotypic classifiers in human autism
• Can identify social deficits and behavioural
repetitiveness in mice
• E.g., mice from C57BL/6J and FVB/NJ, but not
A/J, BALB/cByJ or BTBR T+tf/J inbred strains
show significant preferences to be with other mice
than alone
e.g., RELN
• RELN associated with human autism
• Loss of Reln function in mice leads to
motor impairment, increased anxiety,
learning deficits, abnormal neuroanatomy
• Reeler mouse pups show markedly lower
rates of ultrasonic vocalizations (used by
mothers)
e.g. 5HT
• Genes for 5HT signaling identified in
human autism (e.g., SLC6A4)
• Mouse models often involve targeted
disruptions of 5HT pathway
• Some mutant mouse lines for 5HT pathway
• Behavioural changes related to anxiety,
depression, aggression, spatial memory,
response to reward
e.g. PTEN
• Neuron-specific ablation of Pten in
embryonic mice
– As adults, show low social approach and
increased activity in novel environments
• Pten-null mice show progressive
macrocephaly, dendritic hypertrophy,
ectopic dendrites, increased spine density
Attention-Deficit and Disruptive
Behaviour Disorders
• Attention deficit hyperactivity disorder (ADHD)
–
–
–
–
Substantially heritable
Restless, poor attention span, impulsive
~4% of 6-12 year olds
Boys outnumber girls
• Conduct disorder
– Only modest heritability, when occurring in absence of
overactivity/inattention
– Aggression to people and animals, destruction of
property, deceitfulness, violation of rules
– May be reclassified as antisocial personality disorder
once child passes age 18
ADHD
• 5% risk for first-degree relatives
– Risk higher if ADHD in proband continues into
adulthood
• Heritability of about 76%; shared
environment negligible
• Substantial genetic overlap between the AD
and HD components in this disorder
Conduct Disorder
• 5-10% of children and adolescents meet diagnostic
criteria
• Boys greatly outnumber girls
• MZ concordance, 87%; DZ concordance, 72%
– Only modest heritability, but high shared environment
component
– Should ADHD and CD really be grouped together in
DSM-IV?
Overlap
• Latent class analysis technique
• Without a hyperactivity component, N.Sig. genetic
contribution to conduct disorder
– But shared environment effect very significant
• What ADHD and conduct problems share is
largely due to genetics; what conduct problems
don’t share with ADHD due to environment
• Antisocial behaviour also a factor complicating
interpretation
– Aggressive antisocial behaviour more heritable than
nonaggressive antisocial behaviour
Genes
• Dopamine pathway likely involved
• Dopamine transport gene DAT1 was
investigated early on, but …poor replication
• Two other dopamine receptor genes, DRD4
and DRD5 are now considered quite likely
• But, another 30 candidate genes also
proposed, with mixed results
Autism Spectrum Disorder and
ADHD
• Core diagnostic symptoms do not explicitly
overlap
• However, high levels of comorbidity
between ASD and ADHD reported
Ronald et al. (2008)
• Used Twins Early Development Study, a
UK sample of twins born 1994-96 as
sample
• Phenotypic overlap
– Behavioural criterial, parental and teacher
assessment
– 41% of unrelated ASD children also had
suspected ADHD
– 22% of unrelated ADHD children met criteria
for ASD
• Genetic overlap
– Assessed as quantitative traits, extremes
analysis, and categorical cases
– Genetic correlations estimated at 0.5 or higher
– Moderate degree of overlap between genetic
influences on autistic and ADHD traits;
remainder of genetic influences specific to each
– Over 72% of phenotypic correlation explained
by genetic influences; co-occurrence of autistic
and ADHD bethaviours mostly due to genetic
factors affecting both behaviour types
Childhood Anxiety Disorders
• Three components comparable to adult
anxiety disorders
– Generalized anxiety
– Fears
– Obsessive-compulsive behaviours
• Two specific to childhood
– Separation anxiety
– Shyness/inhibition
Heritability
Shyness/inhibition
Obsessive-compulsive
Generalized anxiety
Fears
Separation anxiety
Heritability
75%
65%
40%
40%
40%
Shared Environment?
no
no
no
10%
35%
• Five components only moderately correlated genetically
• Obsessive-compulsive behaviours least related to the
others genetically