1. Behavioral Genetics Jeffrey Clothier, M.D.

2. Objectives Describe the genetic methods applied to behavior Describe role of genetics and environment in conditions such as MR, IQ, Substance abuse, schizophrenia, affective disorders, and dementing illnesses Describe the value of twin studies and adoption studies in behavioral genetic studies Define heritability

3. Methods of Genetic investigations Transmission studies Family Twin Adoption Pedigree analysis and linkage studies Pedigree and genetic markers Molecular studies Point is to try and predict who will get sick

4. Family studies Describe risk of occurrence of disease in two related at risk persons concordance rate is related to shared characteristics genetic and environmental Heritability -A measure of the relative influence of genetics to overall family transmission

5. Twin studies rare but precious resource for understanding genetic influences Monozygote twins are 100% genetic and 100% environmental “ideally” Dizygote twins are 50% genetic and 100% environmental “ideally” Difference b/w DZ and MZ concordance rates is a measure of genetic influence

6. Adoption studies-control environmental factors Adoptee’s family method(index case is the child) calculates concordance in parents of index case needs information about adoptive and biologic parents greater risk in biologic parents than adoptive parents suggest genetic factors

7. Adoption studies (cont) Adoptees study method (index case is the parent) calculates risk to children of index case increased risk to adopted away children of index case over adopted children of controls suggest genetic factors Crossfostering method Compares risk to adoptees whose biologic parents were ill and adoptive parents were normal with adoptees whose biologic parents were normal and adoptive parents were ill.

8. cross fostering method

9. Problems with twin studies Ascertainment-diagnostic criteria adequacy of control phenotypic classification determination of zygosity

10. Pedigree analysis address questions of penetrance and transmission mechanisms single major locus multifactorial-polygenetic phenotype vs. genotype effect of variable penetrance assumption of dominance endophenotypic expression

11. Single major locus transmission Autosomal recessive Wilson’s disease (ceruloplasmin and copper) damage to liver, cornea and basal ganglia Phenylketonuria (phenylalanine hydroxylase) build up of abnormal metabolite (phenylpyruvic acid carrier state is common (1 in 50) endophenotypic expression

12. Single major locus (cont) Autosomal dominant Huntington’s disease (atrophy of the caudate nucleus) chorea and mental disorders appears around mid 30’s Chromosome 4

13. Single Major locus (cont) Sex linked disorders Usually x linked recessive (ex:Lesch-Nyhan syndrome) self mutilation, MR, Uric aciduria mother is the carrier 1/2 of sons have the disease 1/2 of daughter are carriers carrier state can be detected prenatal diagnosis is possible

14. Single major locus (cont) Disorders of gene and chromosome numbers Trisomy 21 (Down’s) XYY more common in jails than society not related to an elevation of testosterone and aggression probably due to a lower intellectual function of XYY patients

15. Personality Cloninger’s 3 dimensional model novelty seeking harm avoidance reward dependence Some traits have a high inheritance antisocial is greater than rheumatoid arthritis Clear role for socialization and environment

16. Intelligence MZ twins scores on IQ tests have a correlation of 80-90% whether reared together or separately DZ twins have correlation of about 50% heritability factor of about 50-70% Inverse relationship of MR offspring and parents

17. Schizophrenia lifetime population risk of 1% risk to sibs and children of index case is 8- 12% risk to parents is 5% may reflect fact that sicker patients don’t marry

18. Schizophrenia (cont) MZ concordance of 40-70% DZ concordance of 8-20% second trimester hypothesis time of neural specialization frontal injury hypothesis

19. Bipolar disorder Lifetime risk about 1% sexes are equally affected risk to 1st degree relative is 8-20% MZ risk-65-70% DZ risk-15% linkage studies suggest chromosome 11 and x-linked

20. Unipolar lifetime risk is 6-10% 2-3 times more common is women risk to first degree relatives is 10-20% MZ risk-40% DZ risk-11% phenotypic expression-undiagnosed bipolar disorder for ex.

21. Alcoholism lifetime risk- 3-5% for men 0.5 - 1% for women 25% of male first degree relatives 3-10% of female first degree relatives

22. Alcoholism twin risk depends on definitions MZ risk- 60% (Swedish studies) 25% (US) DZ risk 30% (Swedish) 12% (US) runs with affective disorders in families

23. Alcoholism RFLP dopamine 2 receptor alleles Dopamine receptor D2 receptor allele known as Taql B1 is reported as a marker for severe familial alcoholism Aldehyde dehydrogenase enzyme which metabolizes alcohol is found in varying degrees of activity in various cultures

24. Alzheimer’s Disease Difficult to study due to death before expression of gene for SDAT 19% risk for 1st degree relatives increases with survival age 50% if you live to 80 y/o

25. SDAT two forms early onset (prior to 65) linked to chromosome 21 Late onset (after 60) linked to chromosome 19