Twin Studies WPA

Dissecting Genetic Vs Environmental Effects

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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 WPA

Twins: Summary of Nine Studies

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MZ twins have a 53% concordance rate, as compared to 15% in DZ twins

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Approximately 70% of the liability to develop schizophrenia is due to nongenetic factors

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Environmental factors play a crucial role in etiology WPA

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Adoption Studies

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Unconfound genes and environment by measuring prevalence in adopted offspring of schizophrenic mothers, as compared to normal mothers

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Both groups are raised by normal parents WPA

Adoption Studies: Results

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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) WPA

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A 21

st

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 WPA

Genes: Some Simple Concepts

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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 WPA

The Six Steps in Understanding Disease Genes

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Finding or locating Cloning Sequencing Identifying the product Identifying the function Identifying how DNA variation in the gene contributes to disease WPA

Linkage Studies

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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) WPA

Some Chromosomal Susceptibility Loci with Several Replications

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1q21-q22 6q21-q22 8q21-q22 However, findings come and go as larger samples are studied WPA

Candidate Gene Approaches

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“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 WPA

The Human Genome Project

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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 APO

e

4 allele and Alzheimer’s disease) WPA

Gene Mutations

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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) WPA

Genes and Environment

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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” WPA

A Genetically Complex Illness

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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 WPA

How Do We Define the Phenotype?

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Clinical symptoms?

Characteristic course and outcome? Cognitive deficits?

Endophenotypic markers This (clinical!) question is perhaps the most important issue in 21 st century genetics WPA

Can We Find a Pathological Marker?

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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?

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What Does the Marker Mark?

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Vulnerability to develop the disorder?

Subthreshold forms of the disorder?

The endophenotype?

The expressed phenotype?

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Some Candidate Markers

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Eye tracking abnormalities Impaired prepulse inhibition Backward masking abnormalities

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Eyeblink conditioning WPA