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Twin StudiesTwin Studies

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Dissecting Genetic Vs Dissecting Genetic Vs Environmental EffectsEnvironmental Effects• Identical twins have identical Identical twins have identical

DNA, while dizygotic twins share DNA, while dizygotic twins share 50% of their DNA50% of their DNA

• If schizophrenia were completely If schizophrenia were completely genetic, concordance rates in genetic, concordance rates in MZ:DZ twins would be 100:50%, MZ:DZ twins would be 100:50%, or 2:1or 2:1

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Twins: Summary of Nine Twins: Summary of Nine StudiesStudies

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

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

• Environmental factors play a Environmental factors play a crucial role in etiologycrucial role in etiology

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Adoption StudiesAdoption Studies

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

• Both groups are raised by Both groups are raised by normal parentsnormal parents

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Adoption Studies: Adoption Studies: ResultsResults

• Heston:Heston: 16.6% schizophrenia in 16.6% schizophrenia in children of ill mothers, 0% for children of ill mothers, 0% for normal mothersnormal mothers

• Kety:Kety: 32% schizophrenia in 32% schizophrenia in children of ill mothers, 18% for children of ill mothers, 18% for normal mothers (this study used normal mothers (this study used a relatively broader definition of a relatively broader definition of illness)illness)

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A 21A 21stst Century View of Century View of GeneticsGenetics

• No longer sees “genes” as static or simple No longer sees “genes” as static or simple phenomenaphenomena

• Genes interact dynamically with one Genes interact dynamically with one another and with cellular and extracellular another and with cellular and extracellular components to regulate body and brain components to regulate body and brain functionsfunctions

• Genes turn on and off (“are expressed”)Genes turn on and off (“are expressed”)• Regulation of gene expression may be as Regulation of gene expression may be as

important a contributor to disease risk as important a contributor to disease risk as genes alonegenes alone

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Genes: Some Simple Genes: Some Simple ConceptsConcepts

• Gene:Gene: a section of DNA that codes for the a section of DNA that codes for the RNA that produces protein productsRNA that produces protein products

• Regulatory genes:Regulatory genes: genes that determine genes that determine when proteins will be producedwhen proteins will be produced

• Gene expression:Gene expression: the process of turning on the process of turning on genes so that they will become activegenes so that they will become active

• Disease risk genes:Disease risk genes: genes that contain a genes that contain a variation in DNA that leads to a change in variation in DNA that leads to a change in gene function that contributes to diseasegene function that contributes to disease

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The Six Steps in The Six Steps in Understanding Disease GenesUnderstanding Disease Genes

• Finding or locatingFinding or locating

• CloningCloning

• SequencingSequencing

• Identifying the productIdentifying the product

• Identifying the functionIdentifying the function

• Identifying how DNA variation in Identifying how DNA variation in the gene contributes to diseasethe gene contributes to disease

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Linkage StudiesLinkage Studies• Also called “reverse genetics,” since Also called “reverse genetics,” since

they assume no prior knowledge of they assume no prior knowledge of disease mechanismdisease mechanism

• DNA from affected families is used to DNA from affected families is used to identify genetic markers (I.e., relatively identify genetic markers (I.e., relatively large chromosomal regions) that large chromosomal regions) that segregate in ill family memberssegregate in ill family members

• The linkage points to the locations of a The linkage points to the locations of a disease genes (chromosomal disease genes (chromosomal susceptibility loci)susceptibility loci)

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Some Chromosomal Some Chromosomal Susceptibility Loci with Susceptibility Loci with

Several ReplicationsSeveral Replications

• 1q21-q221q21-q22

• 6q21-q226q21-q22

• 8q21-q228q21-q22

• However, findings come and go However, findings come and go as larger samples are studiedas larger samples are studied

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Candidate Gene ApproachesCandidate Gene Approaches• ““Forward genetics”Forward genetics”• Begin with genes hypothesized to be related Begin with genes hypothesized to be related

to the disease mechanism (e.g., to the disease mechanism (e.g., neurotransmitters, receptors, regulators of neurotransmitters, receptors, regulators of brain development)brain development)

• Can be studied either in affected families or in Can be studied either in affected families or in transgenic mice (“knockout” or “knock-in”)transgenic mice (“knockout” or “knock-in”)

• Method is handicapped by the large number Method is handicapped by the large number of possible candidates that can be studiedof possible candidates that can be studied

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The Human Genome ProjectThe Human Genome Project• Provides a reference sequence of 3 billion Provides a reference sequence of 3 billion

base pairsbase pairs• Has identified important markers of genetic Has identified important markers of genetic

diversity that may have relevance for diversity that may have relevance for finding disease markers: SNPsfinding disease markers: SNPs

• SNPs (“snips”): single nucleotide SNPs (“snips”): single nucleotide polymorphisms, or mutations in a single polymorphisms, or mutations in a single nucleotide, which may be associated with nucleotide, which may be associated with predisposition to a given disease (e.g., the predisposition to a given disease (e.g., the APOAPO4 allele and Alzheimer’s disease)4 allele and Alzheimer’s disease)

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Gene MutationsGene Mutations• Occur spontaneously during the process of Occur spontaneously during the process of

DNA replicationDNA replication• May also be induced by exogenous sources May also be induced by exogenous sources

(e.g., radiation)(e.g., radiation)• Most are corrected (eliminated) when they Most are corrected (eliminated) when they

occuroccur• Some persist and may lead to disease (e.g., Some persist and may lead to disease (e.g.,

cancer)cancer)• Some may persist and serve as markers of Some may persist and serve as markers of

genetic variation (e.g. SNPS)genetic variation (e.g. SNPS)

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Genes and EnvironmentGenes and Environment• A false dichotomyA false dichotomy• Environmental factors influence genes – Environmental factors influence genes –

mutations, stress and endocrine mutations, stress and endocrine regulation, viruses, etcregulation, viruses, etc

• Genes create a blueprint, but a gene Genes create a blueprint, but a gene must be “turned on” (I.e., be must be “turned on” (I.e., be “expressed”) to exert its influence“expressed”) to exert its influence

• We can potentially prevent diseases by We can potentially prevent diseases by stopping the expression of “bad genes”stopping the expression of “bad genes”

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A Genetically Complex IllnessA Genetically Complex Illness• A “complex” disorder, probably caused by A “complex” disorder, probably caused by

multiple genes, each of which has a small multiple genes, each of which has a small effecteffect

• A genetic predisposition may be released A genetic predisposition may be released by nongenetic (environmental) triggers, by nongenetic (environmental) triggers, such as difficult labor, infections, subtle such as difficult labor, infections, subtle brain injuries, toxins, etcbrain injuries, toxins, etc

• ““Multiple hits” are probably required, with Multiple hits” are probably required, with those affecting adolescent brain those affecting adolescent brain development being most important development being most important

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How Do We Define the How Do We Define the Phenotype?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 This (clinical!) question is perhaps the most

important issue in 21important issue in 21stst century genetics century genetics

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Can We Find a Can We Find a Pathological Marker?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 Only present as a group

difference?difference?• Specific to schizophrenia?Specific to schizophrenia?• Also present in unaffected family Also present in unaffected family

members?members?

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What Does the Marker What Does the Marker Mark?Mark?

• Vulnerability to develop the Vulnerability to develop the disorder?disorder?

• Subthreshold forms of the Subthreshold forms of the disorder?disorder?

• The endophenotype?The endophenotype?

• The expressed phenotype?The expressed phenotype?

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Some Candidate MarkersSome Candidate Markers

• Eye tracking abnormalitiesEye tracking abnormalities

• Impaired prepulse inhibitionImpaired prepulse inhibition

• Backward masking Backward masking abnormalitiesabnormalities

• Eyeblink conditioningEyeblink conditioning