1. WPA Twin Studies

2. WPA Dissecting Genetic Vs Environmental Effects Identical twins have identical DNA, while dizygotic twins share 50% of their DNAIdentical twins have identical DNA, while dizygotic twins share 50% of their DNA If schizophrenia were completely genetic, concordance rates in MZ:DZ twins would be 100:50%, or 2:1If schizophrenia were completely genetic, concordance rates in MZ:DZ twins would be 100:50%, or 2:1

3. WPA Twins: Summary of Nine Studies MZ twins have a 53% concordance rate, as compared to 15% in DZ twinsMZ twins have a 53% concordance rate, as compared to 15% in DZ twins Approximately 70% of the liability to develop schizophrenia is due to nongenetic factorsApproximately 70% of the liability to develop schizophrenia is due to nongenetic factors Environmental factors play a crucial role in etiologyEnvironmental factors play a crucial role in etiology

4. WPA

5. WPA

6. WPA Adoption Studies Unconfound genes and environment by measuring prevalence in adopted offspring of schizophrenic mothers, as compared to normal mothersUnconfound genes and environment by measuring prevalence in adopted offspring of schizophrenic mothers, as compared to normal mothers Both groups are raised by normal parentsBoth groups are raised by normal parents

7. WPA Adoption Studies: Results Heston: 16.6% schizophrenia in children of ill mothers, 0% for normal mothersHeston: 16.6% schizophrenia in children of ill mothers, 0% for normal mothers Kety: 32% schizophrenia in children of ill mothers, 18% for normal mothers (this study used a relatively broader definition of illness)Kety: 32% schizophrenia in children of ill mothers, 18% for normal mothers (this study used a relatively broader definition of illness)

8. WPA A 21 st Century View of Genetics No longer sees “genes” as static or simple phenomenaNo longer sees “genes” as static or simple phenomena Genes interact dynamically with one another and with cellular and extracellular components to regulate body and brain functionsGenes interact dynamically with one another and with cellular and extracellular components to regulate body and brain functions Genes turn on and off (“are expressed”)Genes turn on and off (“are expressed”) Regulation of gene expression may be as important a contributor to disease risk as genes aloneRegulation of gene expression may be as important a contributor to disease risk as genes alone

9. WPA Genes: Some Simple Concepts Gene: a section of DNA that codes for the RNA that produces protein productsGene: a section of DNA that codes for the RNA that produces protein products Regulatory genes: genes that determine when proteins will be producedRegulatory genes: genes that determine when proteins will be produced Gene expression: the process of turning on genes so that they will become activeGene expression: the process of turning on genes so that they will become active Disease risk genes: genes that contain a variation in DNA that leads to a change in gene function that contributes to diseaseDisease risk genes: genes that contain a variation in DNA that leads to a change in gene function that contributes to disease

10. WPA The Six Steps in Understanding Disease Genes Finding or locatingFinding or locating CloningCloning SequencingSequencing Identifying the productIdentifying the product Identifying the functionIdentifying the function Identifying how DNA variation in the gene contributes to diseaseIdentifying how DNA variation in the gene contributes to disease

11. WPA Linkage Studies Also called “reverse genetics,” since they assume no prior knowledge of disease mechanismAlso called “reverse genetics,” since they assume no prior knowledge of disease mechanism DNA from affected families is used to identify genetic markers (I.e., relatively large chromosomal regions) that segregate in ill family membersDNA from affected families is used to identify genetic markers (I.e., relatively large chromosomal regions) that segregate in ill family members The linkage points to the locations of a disease genes (chromosomal susceptibility loci)The linkage points to the locations of a disease genes (chromosomal susceptibility loci)

12. WPA Some Chromosomal Susceptibility Loci with Several Replications 1q21-q221q21-q22 6q21-q226q21-q22 8q21-q228q21-q22 However, findings come and go as larger samples are studiedHowever, findings come and go as larger samples are studied

13. WPA Candidate Gene Approaches “Forward genetics”“Forward genetics” Begin with genes hypothesized to be related to the disease mechanism (e.g., neurotransmitters, receptors, regulators of brain development)Begin with genes hypothesized to be related to the disease mechanism (e.g., neurotransmitters, receptors, regulators of brain development) Can be studied either in affected families or in transgenic mice (“knockout” or “knock-in”)Can be studied either in affected families or in transgenic mice (“knockout” or “knock-in”) Method is handicapped by the large number of possible candidates that can be studiedMethod is handicapped by the large number of possible candidates that can be studied

14. WPA The Human Genome Project Provides a reference sequence of 3 billion base pairsProvides a reference sequence of 3 billion base pairs Has identified important markers of genetic diversity that may have relevance for finding disease markers: SNPsHas identified important markers of genetic diversity that may have relevance for finding disease markers: SNPs SNPs (“snips”): single nucleotide polymorphisms, or mutations in a single nucleotide, which may be associated with predisposition to a given disease (e.g., the APO  4 allele and Alzheimer’s disease)SNPs (“snips”): single nucleotide polymorphisms, or mutations in a single nucleotide, which may be associated with predisposition to a given disease (e.g., the APO  4 allele and Alzheimer’s disease)

15. WPA Gene Mutations Occur spontaneously during the process of DNA replicationOccur spontaneously during the process of DNA replication May also be induced by exogenous sources (e.g., radiation)May also be induced by exogenous sources (e.g., radiation) Most are corrected (eliminated) when they occurMost are corrected (eliminated) when they occur Some persist and may lead to disease (e.g., cancer)Some persist and may lead to disease (e.g., cancer) Some may persist and serve as markers of genetic variation (e.g. SNPS)Some may persist and serve as markers of genetic variation (e.g. SNPS)

16. WPA Genes and Environment A false dichotomyA false dichotomy Environmental factors influence genes – mutations, stress and endocrine regulation, viruses, etcEnvironmental factors influence genes – mutations, stress and endocrine regulation, viruses, etc Genes create a blueprint, but a gene must be “turned on” (I.e., be “expressed”) to exert its influenceGenes create a blueprint, but a gene must be “turned on” (I.e., be “expressed”) to exert its influence We can potentially prevent diseases by stopping the expression of “bad genes”We can potentially prevent diseases by stopping the expression of “bad genes”

17. WPA A Genetically Complex Illness A “complex” disorder, probably caused by multiple genes, each of which has a small effectA “complex” disorder, probably caused by multiple genes, each of which has a small effect A genetic predisposition may be released by nongenetic (environmental) triggers, such as difficult labor, infections, subtle brain injuries, toxins, etcA genetic predisposition may be released by nongenetic (environmental) triggers, such as difficult labor, infections, subtle brain injuries, toxins, etc “Multiple hits” are probably required, with those affecting adolescent brain development being most important“Multiple hits” are probably required, with those affecting adolescent brain development being most important

18. WPA How Do We Define the Phenotype? Clinical symptoms?Clinical symptoms? Characteristic course and outcome?Characteristic course and outcome? Cognitive deficits?Cognitive deficits? Endophenotypic markersEndophenotypic markers This (clinical!) question is perhaps the most important issue in 21 st century geneticsThis (clinical!) question is perhaps the most important issue in 21 st century genetics

19. WPA Can We Find a Pathological Marker? Should it be present in all cases?Should it be present in all cases? The majority of cases?The majority of cases? Only present as a group difference?Only present as a group difference? Specific to schizophrenia?Specific to schizophrenia? Also present in unaffected family members?Also present in unaffected family members?

20. WPA What Does the Marker Mark? Vulnerability to develop the disorder?Vulnerability to develop the disorder? Subthreshold forms of the disorder?Subthreshold forms of the disorder? The endophenotype?The endophenotype? The expressed phenotype?The expressed phenotype?

21. WPA Some Candidate Markers Eye tracking abnormalitiesEye tracking abnormalities Impaired prepulse inhibitionImpaired prepulse inhibition Backward masking abnormalitiesBackward masking abnormalities Eyeblink conditioningEyeblink conditioning