Unit 7 Behavioral Genetics: Mechanisms and Mental Pathologies

Behavioral Genetics Overview

0. Behavioral genetics: Behavioral traits = multiple genes + multiple environmental influences Nature vs nurture and twinning exp. vs Adoption exp.

• Quantitative genetics estimates what is due to genetics or environment without specifying what genes or environmental factors are causing the differences.
• Molecular genetics: identifies genes

Adoption Designs in Behavioral Genetics

1. Adoption designs: Parents: The adoptions should be shortly after birth; otherwise the environment won't have the same effect. Same way postnatal environment contributions are so important.

• similarities with biological parents: estimation of the contribution of genetics.
• similarities with adoptive parents: estimation of the contribution of the environment Siblings: We can study either genetic full or half-sibling siblings adopted apart. When talking about environmental siblings: genetically unrelated siblings reared in the same house

Twin Design in Behavioral Genetics

2. Twin design: Twins have a similar DNA, live in a similar environment, same socioeconomic status ... while siblings have many differences.

• Identical twins: monozygotic (MZ)
• Fraternal twins: dizygotic (DZ) same-sex (%50)
• No twin siblings First-degree relatives: 50% genetically related parents, siblings and offspring Equal environment assumptions: prenatal and postnatal

Combined Designs in Behavioral Genetics

3. Combined design: Adoption+family+twin design:

• The Colorado Adoption Project
• Early growth and development study Adoption/twin design: twins adopted apart compared with twins adopted together Families of twins method: twin adults family, children of twins design Half-siblings design

Molecular Genetics: SNPs

4. Molecular genetics: Single nucleotide polymorphisms (SNPs) It tests different traits such as attention skills or IQ; this technique has that trait as a reference therefore you can study each person more easily. Summarizing, it estimates genetics influences directly from measured genotypes rather than indirectly from groups with different degrees of relatedness.

• Limitations: very large samples are required and saliva or blood samples are needed.
• Value: doesn't need special samples and multivariate analysis: overlap between traits or across age.
• Main goal of genetic research: To provide diagnostic classifications based on etiology.

Schizophrenia: Psychopathology and Genetics

5. Schizophrenia: Schizophrenia (SCZ) is the most highly studied area, the most severe form of psychopathology, most debilitating of all disorders. Prevalence: 1% of the population. Common signs and symptoms:

• Persistent abnormal beliefs (delusions)
• Hallucinations (i.e. voices)
• Disorganized speech (i.e. odd associations)
• Negative symptoms (i.e. flat affect, avolition) Diagnosis: last 6 months, we have to wait 6 months until we know what psychosis it is. Onset: late adolescence and early adulthood. When it's early onset in adolescence; it's a gradual but worse prognosis.

Schizophrenia Family Studies

Family Studies Conclusion: evidence shows it is a familial disorder Evidence: 9% for first (6% parents, 9% siblings, 13% off-spring) and 4% for second degree relatives

• First degree relatives: Siblings 9% regardless of which parent has the disorder. If both parents are SCZ, however, 46% When a relative has SQZ, usually there are personal treats that are similar to the symptoms of this illness, even if they haven't been diagnosed. Influential study (Parnas, n=200): offspring were followed until their 40's and this high risk group (schizophrenic mothers); had 16% more chances of having children with SCZ. Therefore, environmental factors can increase the risk of having SCZ; such as birth complications, attention problems, personality disorders, your mom being schizophrenic ...

Schizophrenia Twin Studies

Twin Studies Conclusion: genetics contributes to familial resemblance Evidence: 48% for MZ and 17% for DZ twins. Influential studies:

• Genain MZ female quadruplets: variations in symptomatology / severity
• Co-twin control method (MZ): only one twin diagnosed with the disease due to birth complications, neurological abnormalities, brain structure alterations, DNA methylation differences, inconsistent results for CNV (copy nº variation)
• Discordant identical twins study: same rates of SCZ in first degree relatives of both families.

Schizophrenia Adoption Studies

Adoption Studies Conclusion: genetic influence in schizophrenia Influential studies:

• Leonard Heston (1966): adoptees' study method (parents): 11% of adoptees of schizophrenic mothers developed the disorder
• These results were confirmed by: other studies by using a similar adoptees' study method with experimental controls and mothers/fathers. Genotype Environment interaction evidence: adoptees with schizophrenic parents + adoptive families functioned poorly are more likely to have SCZ

Schizophrenia or Schizophrenias?

5.4. Schizophrenia or schizophrenias? In 1908 it was called the schizophrenias and the classic subtypes were the following: Catatonic (motor alterations), paranoid (persecution delusions) and disorganized (thought disorder and flat affect). However, these weren't supported by genetic research. Evidence:

• More severe SCZ more heritable
• Disorganized type high rate of affected family members The current strategy is to search for endophenotypes. Evidence:
• Structural and functional markers in the brain
• Olfactory, attention and memory deficits
• Smooth pursuit eye tracking; jerky; more negative symptoms
• Neurocognitive and neuropsychological assessments

Schizophrenia Molecular Genetics

5.5. Molecular genetics Conclusion: there are several genes or regions that have significant but small associations with SCZ (multiple genes of small effect) Evidence:

• More robust evidence from 2000 onwards
• Linkage studies: 2q and other 10 regions (i.e. 6p,8q)
• Association studies: candidate gene approach: neuroregulin 1 in chromosome 8, dysbindin at 6p22.3 and genes related to dopamine (lack of replication across individual studies)
• Genome association studies (GWAS): 22 nonoverlapping possible loci and some associations in brain-specific gene enhancers (related to transcription process)
• Interest in rare variants studies: rare and large CNVs

Other Adult Psychopathology

6. Other adult psychopathology: Within other adult psychopathology we can find two different types:

Mood Disorders

6.1. Mood disorders: Conclusion: there are several genes or regions that have significant but small associations with SCZ (multiple genes of small effect) Evidence:

• More robust evidence from 2000 onwards
• Linkage studies: 2q and other 10 regions (i.e. 6p,8q)
• Association studies: candidate gene approach: neuroregulin 1 in chromosome 8, dysbindin at 6p22.3 and genes related to dopamine (lack of replication across individual studies)
• Genome association studies (GWAS): 22 nonoverlapping possible loci and some associations in brain-specific gene enhancers (related to transcription process)
• Interest in rare variants studies: rare and large CNVs

Mood Disorders Family Studies

Family studies Conclusion: moderate genetic influence for MDD and high genetic influence found for BD Evidence: Increased risk for 1st degree relatives: 9% of family risk in both MDD and BD. Is BP a severe form of MDD?

• Family risk is higher for BP (14% vs 0%) but twin studies do not support this hypothesis
• Solution: Identifying associated genes. However, results are inconclusive:
• Shared genetic influence on SCZ, MDD and BP: shared methylenetetrahydrofolate reductase (MTHFR) variant but only in Asian and African populations Are some forms of depression more familial? Little support for reactive vs.endogenous subtypes

Mood Disorders Twin Studies

Twin studies Conclusion: moderate genetic influence for Mood disorders

Are MDD and BD genetically distinct? Note: main aim of genetic research is to provide diagnostic classifications based on etiology. Not supported by a twin study (McGuffin et al., 2003) probably due to lack of power in the analysis (67 pairs with at least 1 twin with BD/244 pairs with at least 1 twin with MDD). This requires molecular genetic studies. Studies of offsprings of identical twins discordant for BP: As seen in SCZ, 10% risk for mood disorder in the offspring of the unaffected twin and the affected twin same liability of the illness

Mood Disorders Adoption Studies

Adoption studies Conclusion: inconclusive results Evidence:

• 1 study: slightly higher risk for mood disorders of biological relatives of the probands and greater rates of alcoholism and attempted of actual suicide.
• 2 more studies: little evidence for genetic influence of depression
• Other studies with adoptees with BP found stronger evidence. Birth parents of the BP adoptees showed 7% rate of BP, 21% rate of MDD supports the hypothesis that BP and MDD are not distinct genetically

SNP-Based Heritability for Mood Disorders

SNP, Based Heritability Conclusion: common SNPs contribute a small amount of variance to depression-related phenotypes. SNPs heritability estimates:

• MDD 32%
• Variability in non somatic depression 21%
• Age at onset 17-51% (sample)
• Variability in response to pharmacological treatment 42-47%
• Symptoms of appetite and insomnia 30%

Identifying Genes for Mood Disorders

Identifying genes Conclusion: more evidence for BP but lack of replication. X linkage seems unlikely MDD: less studied, appears to be less heritable

• Genomewide linkage studies: 15q, 15q25-q26
• GWA studies: no significant associations
• With a severe subtype of MDD: Two loci on chromosome 10 BD: New approach: to investigate the role of those candidate genes on brain activity and psychological functioning.
• Genomewide linkage studies: strong evidence for 13q and 22q and same results in SCZ at 13q and 22q.
• GWA studies: support the previous result BP and SCZ shared common SNPs, although in different regions and also associated with MDD
• Candidate genes: CACNA1C and ANK3 CACNA1C healthy carriers showed lower levels of extraversion and higher harm avoidance, trait anxiety, paranoid ideation and high startle reactivity