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Twin Studies

Twin Studies. Dissecting Genetic Vs Environmental Effects. Identical 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 2:1. Twins: Summary of Nine Studies.

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Twin Studies

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  1. Twin Studies

  2. Dissecting Genetic Vs Environmental Effects • Identical 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 2:1

  3. Twins: Summary of Nine Studies • MZ 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 factors • Environmental factors play a crucial role in etiology

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

  5. Adoption Studies: Results • Heston: 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)

  6. A 21st Century View of Genetics • No 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 functions • Genes turn on and off (“are expressed”) • Regulation of gene expression may be as important a contributor to disease risk as genes alone

  7. Genes: Some Simple Concepts • Gene: a section of DNA that codes for the RNA that produces protein products • Regulatory genes: genes that determine when proteins will be produced • Gene 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 disease

  8. The Six Steps in Understanding Disease Genes • Finding or locating • Cloning • Sequencing • Identifying the product • Identifying the function • Identifying how DNA variation in the gene contributes to disease

  9. Linkage Studies • Also 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 members • The linkage points to the locations of a disease genes (chromosomal susceptibility loci)

  10. Some Chromosomal Susceptibility Loci with Several Replications • 1q21-q22 • 6q21-q22 • 8q21-q22 • However, findings come and go as larger samples are studied

  11. Candidate Gene Approaches • “Forward genetics” • 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”) • Method is handicapped by the large number of possible candidates that can be studied

  12. The Human Genome Project • Provides a reference sequence of 3 billion base pairs • Has 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 APOe4 allele and Alzheimer’s disease)

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

  14. Genes and Environment • A false dichotomy • Environmental 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 influence • We can potentially prevent diseases by stopping the expression of “bad genes”

  15. A Genetically Complex Illness • A “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, etc • “Multiple hits” are probably required, with those affecting adolescent brain development being most important

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

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

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

  19. Some Candidate Markers • Eye tracking abnormalities • Impaired prepulse inhibition • Backward masking abnormalities • Eyeblink conditioning

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