1. Psychopathology

2. Autism ASD: Autism spectrum disorder
“There is from the start an extreme autistic aloneness that, whenever possible, disregards, ignores, shuts out anything that comes to the child from the outside. Direct physical contact or such motion or noise as threatens to disrupt the aloneness is either treated “as if it weren't there” or, if this is no longer sufficient, resented painfully as distressing interference.” (Kanner, 1943, p. 242, emphasis in the original)

3. Diagnostic Criteria (ICD)
A) Persistent deficits in social communication and social interaction
B) Restricted, repetitive patterns of behavior, interests, or activities
C) Symptoms must be present in the early developmental period
D) Symptoms cause clinically significant impairment
E) These disturbances are not better explained by intellectual disability

4. Diagnostic Criteria (DSM-V) Autism spectrum disorder
A. Persistent deficits in social communication and social interaction across multiple contexts
B. Restricted, repetitive patterns of behavior, interests, or activities
C. Symptoms must be present in the early developmental period
D. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.
E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level.

5. Autism: Important Facts
Prevalence: used to be considered rare; now 1/68 births (CDC)
Onset: often problems by 6 – 12 months in looking, vocalizing with others; speech and social interactive skills by 12 – 18 months.
Sex ratio: more boys than girls (4:1), but estimates of the ratio vary
Treatment: partial efficacy of early, intense (25 hours a week), structured intervention with highly trained therapists; no cure
Prognosis: generally poor; c. 10% employed as adults but c. 50% still live with parents; worse prognosis with lower IQ

6. Mendelian “Forms” (i.e., single gene disorders associated with ASD)
FMR1 (Fragile X syndrome); most common single-gene disorder associated with ASD
Rett syndrome
Timothy syndrome
Cortical dysplasia-focal epilepsy (CDFE) syndrome
Activity-dependent neuroprotective protein (ADNP) (Helsmoortel-van der Aa) syndrome
Tuberous Sclerosis

7. Fragile X Syndrome & ASD
Most common single gene associated with ASD
ASD more frequency in FXS boys than girls
FXS with ASD more cognitively impaired; IQ may mediate relation between FXS and ASD
Some maintain the nature of ASD symptoms in FXS is different (e.g., FXS have poor eye contact to avoid social anxiety but still enjoy interacting with people; ASD are disinterested)

8. Rett Syndrome: (Graduate) Normal development till 6 months, then:
Slowed cranial growth
Loss of muscle tone, problems walking
Purposeful hand movements replaced by stereotypic movements
Breathing problems
Seizures
Deterioration in language
Marked social anxiety and social withdrawal
Disinterest in other people
Normal development till 6 months, then:

9. Rhet Syndrome: Cause & Pathophysiology (Graduate)
De novo mutation in MEPC2 (methyl-CpG binding protein 2) gene on the X
Protein called MeCP2
Lethal in males, so virtually all affected are female
Virtually all pathophysiology based on trangenics
MeCP2 may influence chromatin architecture
Interacts with NCOR-SMRT complex (regulatory protein complex)

10. Timothy Syndrome (Graduate) Serious cardiac problems (often lethal)
Webbing of skin between fingers/toes
Seizures
ID, delayed speech & language, impaired communication
De novo mutation in CACNA1C gene (calcium channel)

11. Activity-dependent neuroprotective protein (ADNP) syndrome (Helsmoortel-van der Aa syndrome) (Graduate)
Widespread symptomatology affecting morphology, growth, and the sensory, motor, endocrine, immune, and GI systems
Seizures
Intellectual disability
Hyperactivity
De novo mutation in ADNP gene

12. Tuberous Sclerosis (Graduate)
Benign tumors in multiple systems
Most debilitating are CNS tumors but still enormous variable expressivity, anywhere from lethal to normal functioning
Genetic heterogeneity (two loci = TSC1 (hamatrin) gene and TSC2 (tuberin) gene)
1/3 cases autosomal dominant
Rest de novo mutations

13. Chromosomal Anomalies & ASD (not exhaustive)
1) Duplication in 15q11-13 (Dup 15q syndrome)
Prader-Willi/Angelman area
Seizures, delayed motor, language, cognitive development, impaired communication, ID
Most common chromosomal problem with ASD (about 4% of ASD may have this deletion)
2) 22q11.2 deletion syndrome (DiGeorge syndrome, velo-cardio-facial syndrome)
Many physical abnormalities; epilepsy
Delayed growth, speech, learning  ID
ADHD, ASD, sometimes psychosis
3) 16p11.2 deletion and duplication
Some ok; others with marked developmental and behavioral problems including ID and language problems
4) Xp22.3 deletion
Some case histories have ASD
5) Increased number of non-specific de novo CNVs

14. De novo CNVs more common in ASD than in unaffected siblings
Sanders et a. (2015), Neuron 87:

15. GWAS
A few suggestive leads but nothing certain
Sample sizes still small

16. Schizophrenia Failure to embed in reality
Problems in thinking (thought disorder)
Incoherent speech
Flat or inappropriate affect
Loss of motivation
Delusions
Hallucinations

17. Schizophrenia: Important facts
Lifetime risk c. 1%
Onset: mostly late teens through 20s, but can occur in childhood and after 40
1.4 males to 1 female
Wide variation in course: some recover, but usually poor prognosis
No cure but treatment can help psychotic symptoms
Very high cost to society; major cause of disability

21. Current favored model: Two-threshold multifactorial-3 -2 -1 1 2 3 4
Total Liability
Frequency
Schizotypal
Schizophrenic
Relatives of
Schizophrenics
General
Population

22. and CNVs (microdeletions, indels)
Mendelian forms
and CNVs (microdeletions, indels)

23. Problem with Mendelian “forms” and CNVs for psychopathology
In Alzheimer’s, if you get APP, PSEN1, PSEN2, you get AD; you do not get Pick’s disease, Wernicke-Korsakoff syndrome, or Parkinsons
With BRCA1, BRCA2, you get breast or breast/uterine cancer; you do not get lung or pancreatic cancer
With HNF1A (hepatic nuclear factor 1 alpha), you get diabetes and possibly its consequences; you do not get other disorders
With single gene disorders for psychopathology (including intellectual deficiency), you always get “something else” and do not always get the syndrome

24. Example 1: 22q11.2 deletion syndrome
(AKA DiGeorge syndrome, velocardiofacial syndrome)
Immunodeficiency (75%)
Congenital cardiac anomalies (75%)
Cleft palate and other palatal abnormalities (75%)
Endocrine abnormalities (50%)
Feeding, swallowing problems (30%)
Genitourinary anomalies (30%)
Developmental delays in motor, language, speech
Mean IQ of c. 70. learning disabilities
Higher prevalence of ADHD and ASD in childhood
Psychosis/schizophrenia (25%)
Microdeletion in chromosome 22, band q11.2
Common signs and symptoms (McDonald-McGinn et al., 2015)
Is this gene specific for ASD, AHDH, and schizophrenia?

25. Example 2: Cortical dysplasia-focal epilepsy (CDFE) syndrome
Single gene, autosomal recessive disorder
“Clinically, patients were reported to develop normally until intractable focal seizures began in early childhood (1–9 years old), after which language regression, hyperactivity, impulsive and aggressive behavior, and mental retardation developed in all children. In addition, nearly two-thirds of the patients fulfilled the diagnostic criteria for pervasive developmental delay (PDD), the most generic ASD diagnosis.” Penagarinkano and Geschwind (2013)
Is this a Mendelian form for ASD or is ASD one of many behavioral outcomes?

26. Conclusions:
In a strict sense, there are few, if any, Mendelian forms or CNVs specific for psychopathology
In a loose sense, there are a number of Mendelian disorders and CNVs that have forms of psychopathology as one of several outcomes.

27. Summary of Results in Psychopathology: (oversimplified)
All forms have moderate heritability (h2 = c. 50) with some (schizophrenia) having a high heritability (c )
No single gene, Mendelian forms detected (strict definition)
Some Mendelian forms and CNV/indels have psychopathology as one of several symptoms
De novo mutations increased
Hardly any major loci found
Few established phenocopies
GWAS data suggest hyperpolygenic
Cannot predict risk very well

28. Fertility Paradox
Most forms of psychopathology have reduced fertility (e.g., fertility of schizophrenics = 50% that of normals)
Given that all psychopathology runs in families, the prevalence of these disorders should be decreasing
But they are not and some, e.g., ASD, are increasing

29. Possible Reason = Hyperpolygenicity
Perhaps there are so many genes involved in schizophrenia that new mutations in several of these genes could replenish the loss from selection.
Paraphrase of Erlenmeyer-Kimling lecture, c trying to explain the paradox of high heritability and low fitness in schizophrenia.
See Keller (2006) Brain & Behavioral Science.

30. Frontiers: Endophenotype (“within” phenotype)
A phenotype closer to gene action than the phenotype of study; usually an anatomical, physiological, or biochemical variable.

31. Strategy of Endophenotypes:
Detect genes that influence the endophenotype instead of genes for the disorder.
Examples for schizophrenia:
Ventricular size
Abnormal eye tracking

32. Frontiers: Neuroimaging Endophenotypes

33. Legend for the next two figures
From Heinz et al. (2004). Nature Neuroscience, 8,

34. From Heinz et al. (2004). Nature Neuroscience, 8, 20-21.

35. From Heinz et al. (2004). Nature Neuroscience, 8, 20-21.

36. Legend for next Figure
From Hariri et al. (2005), Arch gen Psychiat 62:

37. From Hariri et al. (2005), Arch gen Psychiat 62:146-152

38. Frontiers: Pathway Analysis What do genes detected in GWAS do?
Psychiatric Genetics Consortium (2014), Nature, 511:
Identified 108 susceptibility loci
Most within/close by coding regions but few (10) in exons
Many expressed in brain
Important areas = dopamine, glutamate, synaptic plasticity, immune systems
Significant enrichment for enhancers
Explains 3.4% of variance in liability