Mendelian Form 1 (.5%)

Mendelian Form 2 (1%)

Mendelian Form 3(1.5%)

Major Locus 1 (8%)

Major Locus 2 (4%)

Polygenic (75%)

Phenocopies (10%)

The Pie of Schizophrenia (Theoretical: Early Molecular Biology)

Mendelian Form 1 (.5%)

Mendelian Form 2 (1%)

Mendelian Form 3(1.5%)

Major Locus 1 (8%)

Major Locus 2 (4%)

Polygenic (75%)

Phenocopies (10%)

The Pie of Schizophrenia (Theoretical: Current)

Table 23.1. Risks for schizophrenia in genetic relatives of schizophrenics. Adapted from Gottesman (1991, Figure 10). Genetic Relation: Type of relation: Risk: General Population 1% Third-degree Cousins 2% Second-degree Uncles/aunts 2% Nieces/nephews 3% Grandchildren 4% Half-siblings 6% First degree Children 13% Parents 6% Siblings 9% DZ twins 17% Identical MZ twins 48%

Specific Genetic Liability-3 -2 -1 0 1 2 3

General Genetic Liability-3 -2 -1 0 1 2 3

Specific Environmental Liability-3 -2 -1 0 1 2 3

Total Liability-3 -2 -1 0 1 2 3

Fre

quen

cy

Sch

izot

ypal

Sch

izop

hre

nic

General Environmental Liability-3 -2 -1 0 1 2 3

-3 -2 -1 0 1 2 3 4

Total Liability

Fre

quen

cy

Schi

zoty

pal

Schi

zoph

ren

ic

Relatives ofSchizophrenics

GeneralPopulation

22.1

22.3

21.1

22.1

232425

21

Schematic of chromosome 6 giving twopotential linkage hotspots.

Summary of Linkage Results in Schizophrenia

From Owen et al., Trends in Genetics (2005), 21, 518-525

Red lines = genome-wide significanceBlue lines = significant in more than 1 sampleRed arrow = possible chromosomal anomoliesYellow = potential candidate genes

Summary of GWAS studies in schizophrenia

Lee et al., Neuro & Biobeh Rev (2012)

GWAS genes of interest in schizophrenia

Replication

Replication

? Replication

“Whilst GWAS have identified new and novel genes that are associated with SZ and BPD, the extent of phenotypic variance that is explained by these genes is disappointingly low.”

Lee et al., Neuro & Biobeh Rev (2012), p. 565

Summary of CNV studiesin schizophrenia

Summary of Results:

• 22q11 microdeletion --> velocardiofacial syndrome (VCFS) aka DiGeorge syndrome; increased risk for mental retardation, autism, bipolar disorder, and schizophrenia.

• only 6 good CNV studies as of 2010 but evidence for rare CNV deletions in 1q21.1 and 15q13.3 which affect psychosis and other behavioral problems

• strong effect, but account for about 1% percent of cases

Tam et al. (2009). Biol Psychiatry; Bassett et al. (2010) Am J PsychiatLee et al., Neuro & Biobeh Rev (2012), p. 565

Lee et al., Neuro & Biobeh Rev (2012)

GeneRegion CNV

Sometimes, CNVs are notgene specific

? Lession: Mucking something up in a region is not good.

Example:Lack of specificity for Schizophrenia

Often, range of psychopathology is even greater.

Summary of Results in Psychiatric Genetics:(oversimplified)

• No single gene, Mendelian forms detected (exception: mental retardation)

• Hardly any major loci found

• Few established phenocopies

• GWAS data suggest very polygenic

• Promising early results for CNVs

Notable Exceptions:

• Many Mendelian forms of mental retardation

• Major Loci: ALD and ALDH & Alcoholism

• Amphetamine psychosis = phenocopy for schizophrenia

Odds ratios for ADHD & 7 repeat allele in DRD4

From 7 meta-analyses on European or mostly European Ancestry

“None of these [5] papers reports any associations thatare formally genome-wide significant after correction formultiple testing.”

Franke, Neale, Faraone (2009). Genome-wide associationstudies in ADHD. Human Genetics, 126:13-50

But a summary of GWAS studies says:

Frontiers:Endophenotypes

Endophenotype:(“within” phenotype)

A phenotype closer to gene action than the phenotype of study; usually an

anatomical, physiological, or biochemical variable.

Strategy of Endophenotypes:

Detect genes that influence the endophenotype insteadof genes for the disorder.

Examples for schizophrenia:

• Ventricular size• Abnormal eye tracking

Frontiers:Genes and Neuroimaging

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

Legend for the next two figures

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

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

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

Legend for next Figure

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

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

Frontiers:Genes-environment

Interaction

From Caspi et al., Science 297-851-854

From Foley et al., Arch gen Psychiat, 61:738-744

From Caspi et al., Science 301, 386-389

Depression as a function of stressful life events and the short-longpolymorphism in the serotonin transporter gene

Frontiers:Rare variants

Paraphrase of Erlenmeyer-Kimling lecture, c. 1972 trying to explain the paradoxof high heritability and low fitness in schizophrenia.See Keller (2006) Brain & Behavioral Science.

Perhaps there are so many genesinvolved in schizophrenia that new mutations

in several of these genes could replenishthe loss from selection.

Rare Variant Hypothesis:

• Could be mutations in a gene or CNVs

• Rare gene mutations hard to find inGWAS.

• Need sequencing to find them.

Future Thought:

Perhaps behavior is the genetics ofbehavior is so polygenic and complex

that the study of genetics is not the bestway to proceed.