GENETICS IN PSYCHIATRYGENETICS IN PSYCHIATRY

PRESENTER – DR. SRIRAM.R, FINAL PRESENTER – DR. SRIRAM.R, FINAL YEAR MD PG PSYCHIATRYYEAR MD PG PSYCHIATRY

CHAIRPERSON – DR. R.RAJKUMAR, CHAIRPERSON – DR. R.RAJKUMAR, ASSOCIATE PROF OF PSYCHIATRYASSOCIATE PROF OF PSYCHIATRY

GENETIC TERMS USED IN PSYCHIATRY

Concordance: the probability that a pair of individuals will both have a certain characteristic, given that one of the pair has the characteristic. For example, twins are concordant when both have or both lack a given trait. (Lewontin,1982)

Heritability: proportion of the variance of a phenotype (disease,trait) that is due to genes, estimated from risks to twins and other relatives

Mendelian disease: caused by a (usually rare) change(mutation) in DNA sequence on one(dominant) or both(recessive) of an individual’s pair of chromosomes

Complex disease: caused by an interaction of multiple genetic and/or environmental factors

Allele: A variant of the similar DNA sequence located at a given locus is called an allele.

Haplotype: collection of specific alleles in a cluster of tightly-linked genes on a chromosome that are likely to be inherited together

Locus: a locus (plural loci) is the specific location of a gene, DNA sequence, or position on a chromosome. Each chromosome carries many genes; humans' estimated 'haploid' protein coding genes are 20,000-25,000, on the 23 different chromosomes. Eg. The chromosomal locus of a gene might be written "6p21.3". Because

"21" refers to "region 2, band 1" this is read as "two one", not as "twenty-one". So the entire locus is "six P two one point three"

Genetic map: The ordered list of loci known for a particular genome is called a genetic map. 

Gene mapping: Gene mapping is the process of determining the locus for a particular biological trait.

Genetic linkage is the tendency of alleles that are located close together on a chromosome to be inherited together during meiosis. Genes whose loci are nearer to each other are less likely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be genetically linked. In other words, the nearer two genes are on a chromosome, the lower is the chance of a swap occurring between them, and the more likely they are to be inherited together.

Linkage disequilibrium(LD): non-random association of alleles at two or more loci that descend from single, ancestral chromosomes (Reich, 2001) A variant that is highly correlated with a truly causal variant will show a similar

statistical association to phenotype. If the LD is widespread, many fewer markers will need to be assayed (Psychiatric

GWAS consortium coordinating committee 2009)

Mutation is a permanent change of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA or other genetic elements

SNP pronounced “snip”( Single nucleotide polymorphism) DNA sequence variation occurring commonly within a population (e.g. 1%) in

which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes

Common SNPs: ≥5% frequency ~10million in the genome- targets of the GWAS Rare SNPs: <1% frequency

Copy-number variations (CNVs)—a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal or, for certain genes, a normal variation in the number of copies of one or more sections of the DNA. CNVs correspond to relatively large regions of the genome that have been deleted

(fewer than the normal number) or duplicated (more than the normal number) on certain chromosomes.

For example, the chromosome that normally has sections in order as A-B-C-D might instead have sections A-B-C-C-D (a duplication of "C") or A-B-D (a deletion of "C").

This variation accounts for roughly 13% of human genomic DNA and each variation may range from about one kilobase (1,000 nucleotide bases) to several megabases in size (Pawel et al, 2010)

Genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS) or common-variant association study (CVAS), is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait. GWAS typically focus on associations between single-nucleotide

polymorphisms (SNPs) and traits like major diseases. compare the DNA of two groups of participants: people with the disease

(cases) and similar people without (controls). Each person gives a sample of DNA, from which millions of genetic variants are read using SNP arrays.

If one type of the variant (one allele) is more frequent in people with the disease, the SNP is said to be "associated" with the disease.

A polygene, multiple factor, multiple gene inheritance, or quantitative gene is a group of non-allelic genes that together influence a phenotypic trait. The precise loci or identities of the non-allelic genes are often unknown to biologists.

The common disease-common variant (often abbreviated CD-CV) hypothesis predicts that common disease-causing alleles, or variants, will be found in all human populations which manifest a given disease. Common variants (not necessarily disease-causing) are known to exist in

coding and regulatory sequences of genes. According to the CD-CV hypothesis, some of those variants lead to

susceptibility to complex polygenic diseases. Each variant at each gene influencing a complex disease will have a small

additive or multiplicative effect on the disease phenotype

Pleiotropy occurs when one gene influences multiple, seemingly unrelated phenotypic traits, an example being phenylketonuria, which is a human disease that affects multiple systems but is caused by one gene defect.

INTRODUCTIONINTRODUCTION

TOPICS IN PSYCHIATRIC GENETICSTOPICS IN PSYCHIATRIC GENETICS

• UNDERLYING CONCEPTSUNDERLYING CONCEPTS• TECHNICAL ASPECTSTECHNICAL ASPECTS• STUDY PRINCIPLES AND METHODSSTUDY PRINCIPLES AND METHODS• FINDINGS IN INDIVIDUAL DISORDERSFINDINGS IN INDIVIDUAL DISORDERS• LIMITATIONS AND CONTROVERSIESLIMITATIONS AND CONTROVERSIES• ENDOPHENOTYPESENDOPHENOTYPES• PREDICTING RESPONSE: PHARMACOGENOMICSPREDICTING RESPONSE: PHARMACOGENOMICS• WHAT WE KNOW: GENETIC COUNSELLINGWHAT WE KNOW: GENETIC COUNSELLING

UNDERLYING CONCEPTSUNDERLYING CONCEPTS

• THE BIOPSYCHOSOCIAL HYPOTHESISTHE BIOPSYCHOSOCIAL HYPOTHESIS• GENE – ENVIRONMENT INTERACTIONGENE – ENVIRONMENT INTERACTION• MENDELIAN GENETICS AND BEYONDMENDELIAN GENETICS AND BEYOND• GENETIC MODELSGENETIC MODELS

THE BIOPSYCHOSOCIAL THE BIOPSYCHOSOCIAL HYPOTHESISHYPOTHESIS

BIOLOGICALCONTRIBUTIONOften geneticallyrelated

PSYCHOLOGICALFACTORS

Traits, coping,defenses

ENVIRONMENTALFACTORS

Family, social,cultural, substances,adverse life events

MENTALILLNESS

GENE-ENVIRONMENT INTERACTIONGENE-ENVIRONMENT INTERACTION

• THE RELATIONSHIP BETWEEN GENES AND ENVIRONMENT IS THE RELATIONSHIP BETWEEN GENES AND ENVIRONMENT IS NON-LINEAR.NON-LINEAR.

• OFTEN, IT IS THE INTERACTION OF ONE OR MORE GENETIC OFTEN, IT IS THE INTERACTION OF ONE OR MORE GENETIC VULNERABILITIES WITH ENVIRONMENTAL FACTORS THAT VULNERABILITIES WITH ENVIRONMENTAL FACTORS THAT DETERMINES ILLNESS.DETERMINES ILLNESS.

• IN OTHER WORDS, BOTH ARE NECESSARY, BUT MAY NOT BE IN OTHER WORDS, BOTH ARE NECESSARY, BUT MAY NOT BE SUFFICIENT TO PRODUCE THE ILLNESS.SUFFICIENT TO PRODUCE THE ILLNESS.

GENE-ENVIRONMENT INTERACTION:GENE-ENVIRONMENT INTERACTION:AN EXAMPLE AN EXAMPLE (CASPI ET AL., 2003)(CASPI ET AL., 2003)

GENETIC CODEPolymorphism of

the serotonintransporter

(5-HTT)

LIFE STRESSORSAdverse life events

in early life

DEPRESSIONin adult life

GENE-ENVIRONMENT INTERACTION: GENE-ENVIRONMENT INTERACTION: A MORE COMPLEX EXAMPLEA MORE COMPLEX EXAMPLE

GENETIC CODEFamily history of

schizophrenia(Gene – COMT? NR1?

CHRNA7? CNR1?)

PERSONALITYschizotypal, “schizotaxia”

CANNABIS USE

“SELF-MEDICATION?” FIRST-

EPISODEPSYCHOSIS

OTHER EXAMPLESOTHER EXAMPLES

• HPA AXIS GENES AND STRESS IN ALCOHOLISM – ACTS AS A HPA AXIS GENES AND STRESS IN ALCOHOLISM – ACTS AS A MAINTAINING FACTOR AND CAUSE FOR RELAPSEMAINTAINING FACTOR AND CAUSE FOR RELAPSE

• THE DOPAMINE D2 RECEPTOR AND SEROTONIN TRANSPORTER THE DOPAMINE D2 RECEPTOR AND SEROTONIN TRANSPORTER GENES IN PTSD – ASSOCIATED WITH VULNERABILITYGENES IN PTSD – ASSOCIATED WITH VULNERABILITY

• MONOAMINE OXIDASE A (MAOMONOAMINE OXIDASE A (MAOAA) GENES AND EARLY LIFE ADVERSITY ) GENES AND EARLY LIFE ADVERSITY – ASSOCIATED WITH ADULT ANTISOCIAL BEHAVIOUR– ASSOCIATED WITH ADULT ANTISOCIAL BEHAVIOUR

MENDELIAN GENETICSMENDELIAN GENETICS

• MORE APPLICABLE TO MORE APPLICABLE TO SINGLE-GENE SINGLE-GENE DISORDERSDISORDERS• PRINCIPLES OF PRINCIPLES OF DOMINANTDOMINANT AND AND RECESSIVERECESSIVE GENES GENES• ALLELESALLELES OF A GENE OF A GENE• GENOTYPE GENOTYPE AND AND PHENOTYPEPHENOTYPE• PRINCIPLE OF PRINCIPLE OF SEGREGATIONSEGREGATION• PRINCIPLE OF PRINCIPLE OF INDEPENDENT ASSORTMENTINDEPENDENT ASSORTMENT• COMMONLY APPLIED IN NEUROPSYCHIATRIC DISORDERSCOMMONLY APPLIED IN NEUROPSYCHIATRIC DISORDERS

MENDELIAN DISORDERS IN PSYCHIATRYMENDELIAN DISORDERS IN PSYCHIATRY

• AUTOSOMAL AUTOSOMAL DOMINANTDOMINANT

HUNTINGTON'S HUNTINGTON'S DISEASEDISEASEFAMILIAL ALZHEIMER'SFAMILIAL ALZHEIMER'S

• AUTOSOMAL AUTOSOMAL RECESSIVERECESSIVE

WILSON'S DISEASEWILSON'S DISEASELYSOSOMAL LYSOSOMAL DISORDERSDISORDERSPHENYLKETONURIAPHENYLKETONURIA

LATER MODIFICATIONS OF MENDEL'S LATER MODIFICATIONS OF MENDEL'S CONCEPTSCONCEPTS

• LINKAGELINKAGE• CO-DOMINANCECO-DOMINANCE• PENETRANCEPENETRANCE• EPISTASISEPISTASIS• HARDY-WEINBERG EQUILIBRIUMHARDY-WEINBERG EQUILIBRIUM• TRINUCLEOTIDE REPEATS TRINUCLEOTIDE REPEATS AND AND ANTICIPATIONANTICIPATION• EPIGENETICS EPIGENETICS AND AND IMPRINTINGIMPRINTING

LINKAGELINKAGE

• AS PER MENDEL'S PRINCIPLES, GENES ARE INHERITED AS PER MENDEL'S PRINCIPLES, GENES ARE INHERITED INDEPENDENTLY (ONE BY ONE) AND NOT IN BLOCKS.INDEPENDENTLY (ONE BY ONE) AND NOT IN BLOCKS.

• HOWEVER, IT HAS BEEN FOUND THAT CERTAIN TRAITS MAY BE HOWEVER, IT HAS BEEN FOUND THAT CERTAIN TRAITS MAY BE INHERITED TOGETHER AND NOT SHOW INDEPENDENT INHERITED TOGETHER AND NOT SHOW INDEPENDENT ASSORTMENT.ASSORTMENT.

• THIS IS DUE TO THEIR PROXIMITY ON THE RELEVANT SEGMENT OF THIS IS DUE TO THEIR PROXIMITY ON THE RELEVANT SEGMENT OF THE CHROMOSOME.THE CHROMOSOME.

• THIS PHENOMENON IS CALLED LINKAGE.THIS PHENOMENON IS CALLED LINKAGE.

LINKAGE DISEQUILBRIUMLINKAGE DISEQUILBRIUM• WE DO NOT KNOW WHICH GENES CAUSE PSYCHIATRIC DISORDERS.WE DO NOT KNOW WHICH GENES CAUSE PSYCHIATRIC DISORDERS.• INSTEAD, WE USE MARKERS SPACED EVENLY ALONG THE GENOTYPE INSTEAD, WE USE MARKERS SPACED EVENLY ALONG THE GENOTYPE

TO LOCALIZE THEM.TO LOCALIZE THEM.• THESE MARKERS MAY BE: THESE MARKERS MAY BE: RESTRICTION FRAGMENT LENGTH RESTRICTION FRAGMENT LENGTH

POLYMORPHISMS ANDPOLYMORPHISMS ANDSINGLE NUCLEOTIDE POLYMORPHISMSSINGLE NUCLEOTIDE POLYMORPHISMS

• MARKERS THAT ARE CLOSE TO A POSSIBLE DISEASE GENE WILL BE MARKERS THAT ARE CLOSE TO A POSSIBLE DISEASE GENE WILL BE INHERITED ALONG WITH IT – THEY SHOW LINKAGEINHERITED ALONG WITH IT – THEY SHOW LINKAGE

• THIS IMPLIES THAT IF THE FREQUENCY OF A PARTICULAR MARKER IS THIS IMPLIES THAT IF THE FREQUENCY OF A PARTICULAR MARKER IS HIGHER IN AFFECTED SUBJECTS THAN CONTROLS, A DISEASE GENE HIGHER IN AFFECTED SUBJECTS THAN CONTROLS, A DISEASE GENE MAY BE CLOSE TO IT.MAY BE CLOSE TO IT.

• THIS PHENOMENON IS CALLED LINKAGE DISEQUILBRIUM, BECAUSE IN A THIS PHENOMENON IS CALLED LINKAGE DISEQUILBRIUM, BECAUSE IN A NORMAL POPULATION, WE WOULD EXPECT EQUAL FREQUENCIES.NORMAL POPULATION, WE WOULD EXPECT EQUAL FREQUENCIES.

CO-DOMINANCECO-DOMINANCE

• IN MENDEL'S MODEL, GENES EXIST AS DOMINANT AND RECESSIVE IN MENDEL'S MODEL, GENES EXIST AS DOMINANT AND RECESSIVE FORMS OR ALLELESFORMS OR ALLELES

• HOWEVER, OTHER MODELS EXIST WHEREIN BOTH GENES MAY BOTH HOWEVER, OTHER MODELS EXIST WHEREIN BOTH GENES MAY BOTH BE EXPRESSED EQUALLY, OR AT LEAST CONCURRENTLY.BE EXPRESSED EQUALLY, OR AT LEAST CONCURRENTLY.

• THIS PHENOMENON IS KNOWN AS CO-DOMINANCE: A COMMON THIS PHENOMENON IS KNOWN AS CO-DOMINANCE: A COMMON EXAMPLE WOULD BE THE ABO BLOOD GROUP GENES.EXAMPLE WOULD BE THE ABO BLOOD GROUP GENES.

PENETRANCEPENETRANCE

• IN MENDEL'S MODEL, A GENE EITHER MANIFESTS AS A GIVEN IN MENDEL'S MODEL, A GENE EITHER MANIFESTS AS A GIVEN PHENOTYPE (1) OR NOT (0).PHENOTYPE (1) OR NOT (0).

• HOWEVER, SOME AUTOSOMAL DOMINANT HUMAN DISORDERS HOWEVER, SOME AUTOSOMAL DOMINANT HUMAN DISORDERS SHOW MARKED VARIANCE IN PHENOTYPE, EVEN WHEN THE SAME SHOW MARKED VARIANCE IN PHENOTYPE, EVEN WHEN THE SAME GENE IS PRESENT.GENE IS PRESENT.

• THIS IS KNOWN AS THIS IS KNOWN AS PENETRANCEPENETRANCE, AND CAN CONFOUND GENETIC , AND CAN CONFOUND GENETIC STUDIES BY OBSCURING THE PATTERN OF INHERITANCE.STUDIES BY OBSCURING THE PATTERN OF INHERITANCE.

EPISTASISEPISTASIS

• SOMETIMES, MORE THAN ONE GENE MAY BE REQUIRED FOR A GIVEN SOMETIMES, MORE THAN ONE GENE MAY BE REQUIRED FOR A GIVEN PHENOTYPE.PHENOTYPE.

• THESE TWO GENES ARE AT DIFFERENT LOCI.THESE TWO GENES ARE AT DIFFERENT LOCI.• THEIR EFFECTS ARE INTERACTIVE, BUT NOT ADDITIVE.THEIR EFFECTS ARE INTERACTIVE, BUT NOT ADDITIVE.• IN OTHER WORDS, GENES A AND B AT DIFFERENT LOCI LEAD TO IN OTHER WORDS, GENES A AND B AT DIFFERENT LOCI LEAD TO

PHENOTYPE C; NEITHER A NOR B ALONE LEAD TO C.PHENOTYPE C; NEITHER A NOR B ALONE LEAD TO C.• THIS IS KNOWN AS GENE-GENE INTERACTION, OR EPISTASIS.THIS IS KNOWN AS GENE-GENE INTERACTION, OR EPISTASIS.

HARDY-WEINBERG EQUILIBRIUMHARDY-WEINBERG EQUILIBRIUM

• SUPPOSE THAT TWO ALLELES P AND Q OF A GENE EXIST, AND THEIR SUPPOSE THAT TWO ALLELES P AND Q OF A GENE EXIST, AND THEIR RELATIVE FREQUENCIES IN A POPULATION ARE RELATIVE FREQUENCIES IN A POPULATION ARE P P AND AND Q.Q.

• THE SUM OF THE SUM OF P P AND AND QQ IS 1. IS 1.• IT CAN BE SHOWN THAT THE FREQUENCY OF GENOTYPES IN THE IT CAN BE SHOWN THAT THE FREQUENCY OF GENOTYPES IN THE

POPULATION WOULD BEPOPULATION WOULD BE PP22 + 2PQ + Q + 2PQ + Q2 2

• THIS IS KNOWN AS THIS IS KNOWN AS HARDY-WEINBERG HARDY-WEINBERG EQUILIBRIUM.EQUILIBRIUM.

AN EXAMPLEAN EXAMPLE

• CONSIDER A GENE M FOR MUSICAL TALENT.CONSIDER A GENE M FOR MUSICAL TALENT.• FORM FORM PP (MORE TALENT) IS PRESENT IN 60% (MORE TALENT) IS PRESENT IN 60% (0.6)(0.6) OF A GIVEN POPULATION. OF A GIVEN POPULATION. P P

ANDAND Q Q ARE CO-DOMINANT.ARE CO-DOMINANT.• Q = 1 – P = 0.4Q = 1 – P = 0.4• IF HARDY-WEINBERG EQUILIBRIUM HOLDS, THE FREQUENCIES WOULD BE:IF HARDY-WEINBERG EQUILIBRIUM HOLDS, THE FREQUENCIES WOULD BE:

PP22 : 0.36 (0.6 X 0.6) – VERY TALENTED : 0.36 (0.6 X 0.6) – VERY TALENTED2PQ : 0.48 (2 X 0.6 X 0.4) – FAIR TALENT2PQ : 0.48 (2 X 0.6 X 0.4) – FAIR TALENTQQ22 : 0.16 (0.4 X 0.4) – LEAST TALENT : 0.16 (0.4 X 0.4) – LEAST TALENT

ASSUMPTIONS IN THE HARDY-ASSUMPTIONS IN THE HARDY-WEINBERG EQUILIBRIUMWEINBERG EQUILIBRIUM

• MATING IS RANDOM – IF GOOD MUSICIANS MATING IS RANDOM – IF GOOD MUSICIANS (PP)(PP) SELECTIVELY SELECTIVELY MARRY GOOD MUSICIANS MARRY GOOD MUSICIANS (PP)(PP), THIS ASSUMPTION DOES NOT , THIS ASSUMPTION DOES NOT HOLD.HOLD.

• THERE IS NO SELECTION – IF GOOD MUSICIANS HAVE A THERE IS NO SELECTION – IF GOOD MUSICIANS HAVE A SHORTER LIFE SPAN OR REDUCED REPRODUCTIVE SHORTER LIFE SPAN OR REDUCED REPRODUCTIVE CAPACITY, CAPACITY, PPPP WOULD BE SELECTED OUT. WOULD BE SELECTED OUT.

• THERE IS NO EMIGRATION – IF POOR MUSICIANS MIGRATE TO THERE IS NO EMIGRATION – IF POOR MUSICIANS MIGRATE TO THE U.S., THE FREQUENCY OF THE U.S., THE FREQUENCY OF QQQQ IN INDIA WOULD FALL IN INDIA WOULD FALL

• THERE ARE NO MUTATIONS (FOR EXAMPLE, CREATING A THERE ARE NO MUTATIONS (FOR EXAMPLE, CREATING A NEW ALLELE NEW ALLELE RR THAT CONFERS MORE TALENT) THAT CONFERS MORE TALENT)

TRINUCLEOTIDETRINUCLEOTIDE REPEATSREPEATS

• CERTAIN GENES ARE NOTICED TO CONTAIN REPEATING SEQUENCES CERTAIN GENES ARE NOTICED TO CONTAIN REPEATING SEQUENCES OF TRINUCLEOTIDE BASES, SUCH AS CAG OR CGG.OF TRINUCLEOTIDE BASES, SUCH AS CAG OR CGG.

• THE NUMBER OF THESE REPEATS AFFECTS THE FUNCTIONING OF THE THE NUMBER OF THESE REPEATS AFFECTS THE FUNCTIONING OF THE GENE AND MAY LEAD TO DISEASE.GENE AND MAY LEAD TO DISEASE.

• THESE DISORDERS ARE KNOWN AS THESE DISORDERS ARE KNOWN AS TRINUCLEOTIDE REPEAT TRINUCLEOTIDE REPEAT DISORDERSDISORDERS..

EXAMPLES OF TRINUCLEOTIDE REPEAT EXAMPLES OF TRINUCLEOTIDE REPEAT DISORDERSDISORDERS

• HUNTINGTON'S DISEASE –HUNTINGTON'S DISEASE – CAG REPEATS IN THE HUNTINGTIN GENE ON CAG REPEATS IN THE HUNTINGTIN GENE ON CHROMOSOME 4.CHROMOSOME 4.

• SPINOCEREBELLAR ATAXIA –SPINOCEREBELLAR ATAXIA – CAG REPEATS ON VARIOUS CHROMOSOMES (6, CAG REPEATS ON VARIOUS CHROMOSOMES (6, 12, 16)12, 16)

• FRAGILE X SYNDROME –FRAGILE X SYNDROME – CGG REPEATS ON THE LONG ARM OF CGG REPEATS ON THE LONG ARM OF CHROMOSOME X.CHROMOSOME X.

• ? SCHIZOPHRENIA –? SCHIZOPHRENIA – ONE GENETIC MODEL OF SCHIZOPHRENIA INVOLVES ONE GENETIC MODEL OF SCHIZOPHRENIA INVOLVES CAG REPEATS AT 6P, 8P AND 22Q, AND PERHAPS OTHER AREASCAG REPEATS AT 6P, 8P AND 22Q, AND PERHAPS OTHER AREAS

NUMBERS AND SEVERITYNUMBERS AND SEVERITY

• THE NUMBER OF REPEATS OFTEN CORRELATES WITH THE THE NUMBER OF REPEATS OFTEN CORRELATES WITH THE PHENOTYPE.PHENOTYPE.

• FOR EXAMPLE, IN HUNTINGTON'S DISEASE, CLINICAL SYMPTOMS FOR EXAMPLE, IN HUNTINGTON'S DISEASE, CLINICAL SYMPTOMS USUALLY APPEAR WHEN THERE USUALLY APPEAR WHEN THERE ARE >38 CAG ARE >38 CAG REPEATS.REPEATS.

• IN FRAGILE X SYNDROME, IN FRAGILE X SYNDROME, <43 CGG REPEATS ARE NORMAL, <43 CGG REPEATS ARE NORMAL, 43-200 ARE CARRIERS, AND >200 HAVE THE CLINICAL 43-200 ARE CARRIERS, AND >200 HAVE THE CLINICAL SYNDROMESYNDROME..

ANTICIPATIONANTICIPATION

• WHEN A TRINUCLEOTIDE REPEAT DISEASE GENE IS TRANSMITTED TO WHEN A TRINUCLEOTIDE REPEAT DISEASE GENE IS TRANSMITTED TO OFFSPRING, THE NUMBER OF REPEATS MAY UNDERGO EXPANSION.OFFSPRING, THE NUMBER OF REPEATS MAY UNDERGO EXPANSION.

• THIS MAY BE RELATED TO THE ORIGIN OF THE GENE – IN THIS MAY BE RELATED TO THE ORIGIN OF THE GENE – IN HUNTINGTON'S, PATERNAL GENES ARE MORE LIKELY TO EXPAND.HUNTINGTON'S, PATERNAL GENES ARE MORE LIKELY TO EXPAND.

• THIS LEADS TO OFFSPRING DEVELOPING THE ILLNESS AT AN EARLIER THIS LEADS TO OFFSPRING DEVELOPING THE ILLNESS AT AN EARLIER AGE AND WITH GREATER SEVERITY; THIS PROCESS IS KNOWN AS AGE AND WITH GREATER SEVERITY; THIS PROCESS IS KNOWN AS ANTICIPATIONANTICIPATION..

EPIGENETICSEPIGENETICS

• THUS FAR, WE HAVE CONSIDERED THE DNA SEQUENCE OF GENES AS BEING THUS FAR, WE HAVE CONSIDERED THE DNA SEQUENCE OF GENES AS BEING OF PRIME IMPORTANCE.OF PRIME IMPORTANCE.

• HOWEVER, GENES IN DNA EXIST IN CHROMOSOMES, ASSOCIATED WITH HOWEVER, GENES IN DNA EXIST IN CHROMOSOMES, ASSOCIATED WITH PROTEINS PROTEINS (HISTONES)(HISTONES)..

• THE CHEMICAL STRUCTURE OF DNA CAN UNDERGO MODIFICATIONS, SUCH AS THE CHEMICAL STRUCTURE OF DNA CAN UNDERGO MODIFICATIONS, SUCH AS METHYLATION, PHOSPHORYLATION, ACETYLATION, ETCMETHYLATION, PHOSPHORYLATION, ACETYLATION, ETC

• THE AMINO ACIDS OF HISTONES CAN ALSO UNDERGO SUCH MODIFICATIONS.THE AMINO ACIDS OF HISTONES CAN ALSO UNDERGO SUCH MODIFICATIONS.• THESE CHANGES DO THESE CHANGES DO NOTNOT ALTER THE SEQUENCE OF NUCLEOTIDES IN GENES. ALTER THE SEQUENCE OF NUCLEOTIDES IN GENES.• HOWEVER, THEY MAY AFFECT THE ACTIVATION AND LEVEL OF EXPRESSION OF HOWEVER, THEY MAY AFFECT THE ACTIVATION AND LEVEL OF EXPRESSION OF

THE RESPECTIVE GENES.THE RESPECTIVE GENES.• THESE PROCESSES ARE COLLECTIVELY CALLED THESE PROCESSES ARE COLLECTIVELY CALLED EPIGENETIC EPIGENETIC

MODIFICATIONSMODIFICATIONS, AND SHARE CERTAIN INTERESTING PROPERTIES, AND SHARE CERTAIN INTERESTING PROPERTIES

EPIGENETICS .VS. “CLASSICAL” EPIGENETICS .VS. “CLASSICAL” GENETICSGENETICS

• MAINTAINED IN SOMATIC CELL REPLICATIONMAINTAINED IN SOMATIC CELL REPLICATION• MAY MAY BE MAINTAINED DURING MEIOSIS, OR MODIFIED, OR BE MAINTAINED DURING MEIOSIS, OR MODIFIED, OR

COMPLETELY REMOVEDCOMPLETELY REMOVED• SUBJECT TO RANDOM OR SUBJECT TO RANDOM OR STOCHASTIC STOCHASTIC EFFECTSEFFECTS• MODIFIABLE BY ENVIRONMENTAL FACTORS, SUCH AS NUTRITION, MODIFIABLE BY ENVIRONMENTAL FACTORS, SUCH AS NUTRITION,

SUBSTANCES OR HORMONESSUBSTANCES OR HORMONES• MODIFICATIONS MODIFICATIONS (EPIMUTATIONS)(EPIMUTATIONS) MAY “REGRESS TO THE MEAN” MAY “REGRESS TO THE MEAN”

WITH AGEWITH AGE

AN EPIGENETIC MODEL OF AN EPIGENETIC MODEL OF SCHIZOPHRENIA SCHIZOPHRENIA (PETRONIS, 2004)(PETRONIS, 2004)

PHENOMENA THAT MAY BE EXPLAINED PHENOMENA THAT MAY BE EXPLAINED BY EPIGENETICS IN PSYCHOSISBY EPIGENETICS IN PSYCHOSIS

• FAMILIAL AND SPORADIC CASESFAMILIAL AND SPORADIC CASES• DISCORDANCE IN MONOZYGOTIC TWINSDISCORDANCE IN MONOZYGOTIC TWINS• COURSE AND RESOLUTION OF THE ILLNESSCOURSE AND RESOLUTION OF THE ILLNESS• EFFECTS OF GENDEREFFECTS OF GENDER• PERSISTENCE OF THE ILLNESS DESPITE PERSISTENCE OF THE ILLNESS DESPITE

EVOLUTIONARY DISADVANTAGESEVOLUTIONARY DISADVANTAGES• NON-REPLICABILITY OF “CLASSICAL” STUDIESNON-REPLICABILITY OF “CLASSICAL” STUDIES• ANTICIPATION AND PARENT-OF-ORIGIN EFFECTSANTICIPATION AND PARENT-OF-ORIGIN EFFECTS

IMPRINTINGIMPRINTING

PATERNAL AND MATERNAL COPIES OF THE SAME GENE PATERNAL AND MATERNAL COPIES OF THE SAME GENE UNDERGO EPIGENETIC MODIFICATIONS.UNDERGO EPIGENETIC MODIFICATIONS.

THIS PROCESS IS CALLED THIS PROCESS IS CALLED IMPRINTINGIMPRINTING, AND LEADS TO , AND LEADS TO DIFFERENTIAL EXPRESSION OF GENES IN THE OFFSPRING DIFFERENTIAL EXPRESSION OF GENES IN THE OFFSPRING DEPENDING ON WHICH COPY IS INHERITED.DEPENDING ON WHICH COPY IS INHERITED.

THIS CAN LEAD TO DIFFERENCES IN ILLNESS EXPRESSION – E.G. THIS CAN LEAD TO DIFFERENCES IN ILLNESS EXPRESSION – E.G. PRADER-WILLIPRADER-WILLI AND AND ANGELMANANGELMAN SYNDROMES HAVE THE SAME SYNDROMES HAVE THE SAME GENETIC MUTATION, BUT DIFFERENT SYMPTOMSGENETIC MUTATION, BUT DIFFERENT SYMPTOMS

GENETIC MODELSGENETIC MODELS

• MENDELIANMENDELIAN• MENDELIAN MENDELIAN WITH VARIABLE PENETRANCEWITH VARIABLE PENETRANCE• MENDELIAN MENDELIAN WITH WITH IMPRINTINGIMPRINTING• OLIGOGENIC –OLIGOGENIC – A SMALL NUMBER OF KEY GENES A SMALL NUMBER OF KEY GENES

INTERACTINGINTERACTING• MIXED –MIXED – A SINGLE MAJOR GENE + OLIGOGENES A SINGLE MAJOR GENE + OLIGOGENES• POLYGENIC –POLYGENIC – MULTIPLE GENES OF SMALL EFFECT MULTIPLE GENES OF SMALL EFFECT

HERITABILITYHERITABILITY

TECHNIQUES UTILIZED IN GENETIC TECHNIQUES UTILIZED IN GENETIC STUDIESSTUDIES

• CLEAVAGE OF DNA AT SPECIFIC SITES BY CLEAVAGE OF DNA AT SPECIFIC SITES BY RESTRICTION RESTRICTION ENDONUCLEASESENDONUCLEASES

• USING USING MARKERS –MARKERS – RFLPS, SNPS, TRINUCLEOTIDE REPEATS RFLPS, SNPS, TRINUCLEOTIDE REPEATS• HYBRIDIZATIONHYBRIDIZATION OF MARKERS AND COMPLEMENTARY OF MARKERS AND COMPLEMENTARY

SEQUENCES – FLUORESCENT, IMMUNE, ETC.SEQUENCES – FLUORESCENT, IMMUNE, ETC.• KARYOTYPINGKARYOTYPING AND OTHER CYTOGENETIC METHODS AND OTHER CYTOGENETIC METHODS• EXAMINING SEQUENCES OF DNA THAT HAVE BEEN CONSERVED EXAMINING SEQUENCES OF DNA THAT HAVE BEEN CONSERVED

EVOLUTIONARILY, OR EVOLUTIONARILY, OR HAPLOTYPESHAPLOTYPES

TECHNIQUES UTILIZED IN GENETIC TECHNIQUES UTILIZED IN GENETIC STUDIESSTUDIES

• THE THE POLYMERASE CHAIN REACTIONPOLYMERASE CHAIN REACTION – USING BACTERIAL DNA – USING BACTERIAL DNA POLYMERASE TO AMPLIFY SEQUENCESPOLYMERASE TO AMPLIFY SEQUENCES

• RECOMBINANT DNA TECHNOLOGYRECOMBINANT DNA TECHNOLOGY TO EXAMINE GENE EXPRESSION AND TO EXAMINE GENE EXPRESSION AND PRODUCTSPRODUCTS

• KNOCK-OUTKNOCK-OUT AND AND TRANSGENICTRANSGENIC ANIMAL MODELS TO STUDY THE EFFECTS ANIMAL MODELS TO STUDY THE EFFECTS OF A SINGLE GENE OR GENE PRODUCTOF A SINGLE GENE OR GENE PRODUCT

• USING THE MAP OF THE HUMAN GENOME FROM THE USING THE MAP OF THE HUMAN GENOME FROM THE HUMAN GENOME HUMAN GENOME PROJECTPROJECT

• MICRO-ARRAYMICRO-ARRAY TECHNIQUES, WHICH USE SEMICONDUCTOR TECHNIQUES TECHNIQUES, WHICH USE SEMICONDUCTOR TECHNIQUES OR ROBOTICS TO AMPLIFY AND EXAMINE MARKERS, AND TO MEASURE OR ROBOTICS TO AMPLIFY AND EXAMINE MARKERS, AND TO MEASURE MRNA LEVELSMRNA LEVELS

• POSTMORTEM POSTMORTEM STUDIES ON HUMAN BRAINSSTUDIES ON HUMAN BRAINS• NEWER STATISTICAL METHODS - NEWER STATISTICAL METHODS - BIOINFORMATICSBIOINFORMATICS

CLASSICAL PSYCHIATRIC GENETICSCLASSICAL PSYCHIATRIC GENETICSDOES THE DISORDER RUN IN FAMILIES? Family studies – establish familiality

IS FAMILIALITY DUE TO GENES OR THE ENVIRONMENT?Twin studies – examine concordance rates in twin pairs

HOW MUCH DO GENES AND THE ENVIRONMENT CONTRIBUTE?Adoption studies – separate genetic and environmental contributions

WHICH GENES ARE INVOLVED?Linkage and association studies

HOW DO THE GENES PRODUCE THE DISEASE? Molecular genetics

MORE RECENT CONCEPTSMORE RECENT CONCEPTS

• ENDOPHENOTYPE APPROACHESENDOPHENOTYPE APPROACHES

• ANIMAL MODELS – KNOCKOUT MICE, ETC.ANIMAL MODELS – KNOCKOUT MICE, ETC.

• PHARMACOGENETICS AND PHARMACOGENOMICSPHARMACOGENETICS AND PHARMACOGENOMICS

THE FIRST STEP: FAMILY STUDIESTHE FIRST STEP: FAMILY STUDIES

• FAMILY STUDIES ESTABLISH THAT A GIVEN DISORDER RUNS IN FAMILY STUDIES ESTABLISH THAT A GIVEN DISORDER RUNS IN FAMILIES.FAMILIES.

• HOWEVER, THEY DO NOT DIRECTLY SHOW WHETHER THIS IS DUE HOWEVER, THEY DO NOT DIRECTLY SHOW WHETHER THIS IS DUE TO GENES OR ENVIRONMENTAL FACTORS.TO GENES OR ENVIRONMENTAL FACTORS.

• IN FAMILY STUDIES, AFFECTED INDIVIDUALS IN FAMILY STUDIES, AFFECTED INDIVIDUALS (PROBANDS)(PROBANDS) ARE ARE SELECTED, AND THEIR FAMILIES ARE EXAMINED FOR A GIVEN SELECTED, AND THEIR FAMILIES ARE EXAMINED FOR A GIVEN DISORDER.DISORDER.

• THEIR RATES OF THE DISORDER ARE THEN COMPARED WITH THEIR RATES OF THE DISORDER ARE THEN COMPARED WITH EITHER A CONTROL GROUP OR THE POPULATION.EITHER A CONTROL GROUP OR THE POPULATION.

TWO TYPES OF FAMILY STUDIESTWO TYPES OF FAMILY STUDIES

• FAMILY HISTORY METHOD: FAMILY HISTORY METHOD: THE PROBAND IS THE PROBAND IS INTERVIEWED, AND INFORMATION ABOUT MENTAL INTERVIEWED, AND INFORMATION ABOUT MENTAL ILLNESS IN RELATIVES IS COLLECTED. SIMPLER, ILLNESS IN RELATIVES IS COLLECTED. SIMPLER, BUT LESS RELIABLE; UNDERESTIMATES TRUE BUT LESS RELIABLE; UNDERESTIMATES TRUE RATES.RATES.

• FAMILY STUDY METHOD: FAMILY STUDY METHOD: ALL AVAILABLE ALL AVAILABLE RELATIVES ARE INTERVIEWED DIRECTLY. TIME-RELATIVES ARE INTERVIEWED DIRECTLY. TIME-CONSUMING, BUT MORE RELIABLE.CONSUMING, BUT MORE RELIABLE.

GENETIC DISTANCEGENETIC DISTANCE

• FAMILY STUDIES CANNOT DIRECTLY GIVE ESTIMATES OF GENETIC FAMILY STUDIES CANNOT DIRECTLY GIVE ESTIMATES OF GENETIC CONTRIBUTIONS.CONTRIBUTIONS.

• HOWEVER, IF THE RATE OF DISORDERS FALLS AS THE AMOUNT OF HOWEVER, IF THE RATE OF DISORDERS FALLS AS THE AMOUNT OF SHARED DNA BETWEEN RELATIVES DECREASES (INCREASED SHARED DNA BETWEEN RELATIVES DECREASES (INCREASED GENETIC GENETIC DISTANCEDISTANCE), A GENETIC COMPONENT IS LIKELY.), A GENETIC COMPONENT IS LIKELY.

• A FAMILY STUDY OF OCD FOUND RATES OF 7% IN FIRST-DEGREE A FAMILY STUDY OF OCD FOUND RATES OF 7% IN FIRST-DEGREE RELATIVES, AND 2% IN SECOND-DEGREE RELATIVES.RELATIVES, AND 2% IN SECOND-DEGREE RELATIVES.

• THE POPULATION RATE IS 2-3%.THE POPULATION RATE IS 2-3%.• THIS SUGGESTS THAT:THIS SUGGESTS THAT:

1. OCD IS FAMILIAL.1. OCD IS FAMILIAL.2. A GENETIC CONTRIBUTION IS LIKELY.2. A GENETIC CONTRIBUTION IS LIKELY.

TWIN STUDIESTWIN STUDIES• MONOZYGOTIC (MZ) TWINS SHARE 100% GENETIC MATERIAL, WHILE MONOZYGOTIC (MZ) TWINS SHARE 100% GENETIC MATERIAL, WHILE

DIZYGOTIC (DZ) TWINS SHARE AS MUCH AS BROTHERS OR SISTERS (50%)DIZYGOTIC (DZ) TWINS SHARE AS MUCH AS BROTHERS OR SISTERS (50%)• CONCORDANCECONCORDANCE IS DEFINED AS THE POSSIBILITY THAT BOTH MEMBERS OF A IS DEFINED AS THE POSSIBILITY THAT BOTH MEMBERS OF A

TWIN PAIR WILL HAVE THE DISORDER BEING STUDIED.TWIN PAIR WILL HAVE THE DISORDER BEING STUDIED.• IT IS ASSUMED THAT MZ AND DZ TWINS GROW UP IN SIMILAR IT IS ASSUMED THAT MZ AND DZ TWINS GROW UP IN SIMILAR

ENVIRONMENTS (THE ENVIRONMENTS (THE “EQUAL-ENVIRONMENT ASSUMPTION”“EQUAL-ENVIRONMENT ASSUMPTION”))• IF A DISORDER IS DETERMINED BY ENVIRONMENTAL FACTORS, IF A DISORDER IS DETERMINED BY ENVIRONMENTAL FACTORS,

CONCORDANCE RATES IN MZ AND DZ TWINS SHOULD BE SIMILAR.CONCORDANCE RATES IN MZ AND DZ TWINS SHOULD BE SIMILAR.• ON THE OTHER HAND, IF IT IS GENETICALLY DETERMINED, CONCORDANCE ON THE OTHER HAND, IF IT IS GENETICALLY DETERMINED, CONCORDANCE

SHOULD BE MORE IN MZ THAN IN DZ TWINS.SHOULD BE MORE IN MZ THAN IN DZ TWINS.• THE EXTENT OF CONCORDANCE PROVIDES AN ESTIMATE OF THE GENETIC THE EXTENT OF CONCORDANCE PROVIDES AN ESTIMATE OF THE GENETIC

CONTRIBUTION.CONTRIBUTION.

AN EXAMPLE OF TWIN STUDIESAN EXAMPLE OF TWIN STUDIES

• A STUDY FINDS THAT THE CONCORDANCE FOR BIPOLAR DISORDER A STUDY FINDS THAT THE CONCORDANCE FOR BIPOLAR DISORDER IN MZ TWINS IS 60%, AND IN DZ TWINS 20%IN MZ TWINS IS 60%, AND IN DZ TWINS 20%

• THIS INDICATES THAT GENETIC FACTORS ARE LIKELY MORE THIS INDICATES THAT GENETIC FACTORS ARE LIKELY MORE IMPORTANT (NUMERICALLY) THAN ENVIRONMENTAL FACTORS IN IMPORTANT (NUMERICALLY) THAN ENVIRONMENTAL FACTORS IN BIPOLAR DISORDER.BIPOLAR DISORDER.

• HOWEVER, THE <100% CONCORDANCE INDICATES THAT THERE IS HOWEVER, THE <100% CONCORDANCE INDICATES THAT THERE IS STILL A 40% CONTRIBUTION FROM ENVIRONMENTAL FACTORS.STILL A 40% CONTRIBUTION FROM ENVIRONMENTAL FACTORS.

ADOPTION STUDIESADOPTION STUDIES• ADOPTION STUDIES BROADLY SEEK TO DETERMINE WHETHER HEREDITY (NATURE) ADOPTION STUDIES BROADLY SEEK TO DETERMINE WHETHER HEREDITY (NATURE)

OR ENVIRONMENT (NURTURE) ARE MORE IMPORTANT IN A GIVEN DISORDER.OR ENVIRONMENT (NURTURE) ARE MORE IMPORTANT IN A GIVEN DISORDER.• THEY RELY ON THE ASSUMPTION OF THEY RELY ON THE ASSUMPTION OF “NO SELECTIVE PLACEMENT”“NO SELECTIVE PLACEMENT” - THAT IS, - THAT IS,

THAT THE ENVIRONMENT PROVIDED BY ADOPTIVE PARENTS IS ONLY RANDOMLY THAT THE ENVIRONMENT PROVIDED BY ADOPTIVE PARENTS IS ONLY RANDOMLY SIMILAR TO THAT OF THE BIOLOGICAL PARENTS.SIMILAR TO THAT OF THE BIOLOGICAL PARENTS.

• CONSIDER TWO GROUPS OF ADOPTED CHILDREN, NAMED A AND B.CONSIDER TWO GROUPS OF ADOPTED CHILDREN, NAMED A AND B.• GROUP A ARE CHILDREN OF PATIENTS WITH A GIVEN DISORDER (SAY DEPRESSION).GROUP A ARE CHILDREN OF PATIENTS WITH A GIVEN DISORDER (SAY DEPRESSION).• GROUP B ARE CHILDREN WHOSE ADOPTIVE PARENTS HAVE THE GIVEN DISORDER, GROUP B ARE CHILDREN WHOSE ADOPTIVE PARENTS HAVE THE GIVEN DISORDER,

OR CONTROLS.OR CONTROLS.• WE NOW COMPARE THE RATES OF DEPRESSION IN GROUPS A AND B, AS WELL AS WE NOW COMPARE THE RATES OF DEPRESSION IN GROUPS A AND B, AS WELL AS

THE AGREEMENT BETWEEN THEIR DIAGNOSES AND THOSE OF BIOLOGICAL AND THE AGREEMENT BETWEEN THEIR DIAGNOSES AND THOSE OF BIOLOGICAL AND ADOPTED PARENTS.ADOPTED PARENTS.

ADOPTION STUDIESADOPTION STUDIES

• IN OUR EXAMPLE, GROUP A HAVE A (PRESUMED) GENETIC IN OUR EXAMPLE, GROUP A HAVE A (PRESUMED) GENETIC LIABILITY TO DEPRESSION, BUT NO ENVIRONMENTAL LOADING.LIABILITY TO DEPRESSION, BUT NO ENVIRONMENTAL LOADING.

• THE OPPOSITE HOLDS GOOD FOR GROUP B.THE OPPOSITE HOLDS GOOD FOR GROUP B.• MEASURING THE RATES OF THE DISORDER IN GROUPS WOULD MEASURING THE RATES OF THE DISORDER IN GROUPS WOULD

GIVE US A MEASURE OF WHETHER ENVIRONMENTAL OR GIVE US A MEASURE OF WHETHER ENVIRONMENTAL OR GENETIC VULNERABILITY PLAYS A GREATER ROLE.GENETIC VULNERABILITY PLAYS A GREATER ROLE.

AN EXAMPLE OF ADOPTION STUDYAN EXAMPLE OF ADOPTION STUDY

• A STUDY IS DONE EXAMINING 50 CHILDREN OF ALCOHOLICS WHO A STUDY IS DONE EXAMINING 50 CHILDREN OF ALCOHOLICS WHO ARE ADOPTED, AND 50 CHILDREN WHOSE ADOPTIVE PARENTS ARE ADOPTED, AND 50 CHILDREN WHOSE ADOPTIVE PARENTS HAVE ALCOHOLISM.HAVE ALCOHOLISM.

• THE STUDY FINDS THAT RATES OF ALCOHOLISM ARE 12% IN THE THE STUDY FINDS THAT RATES OF ALCOHOLISM ARE 12% IN THE FIRST GROUP, AND 6% IN THE SECOND GROUP.FIRST GROUP, AND 6% IN THE SECOND GROUP.

• THE GREATER AGREEMENT WITH THE BIOLOGICAL PARENTS' THE GREATER AGREEMENT WITH THE BIOLOGICAL PARENTS' DIAGNOSIS POINTS TO A GENETIC COMPONENT.DIAGNOSIS POINTS TO A GENETIC COMPONENT.

FINDING THE GENESFINDING THE GENES

• ONCE THE FAMILIALITY AND GENETIC COMPONENT OF A GIVEN DISORDER ARE ONCE THE FAMILIALITY AND GENETIC COMPONENT OF A GIVEN DISORDER ARE ESTABLISHED, THE GENE OR GENES RESPONSIBLE MUST BE IDENTIFIED.ESTABLISHED, THE GENE OR GENES RESPONSIBLE MUST BE IDENTIFIED.

• THIS IS DONE BY MEANS OF FOUR METHODS:THIS IS DONE BY MEANS OF FOUR METHODS:1. LINKAGE ANALYSIS1. LINKAGE ANALYSIS2. ASSOCIATION ANALYSIS2. ASSOCIATION ANALYSIS3. CANDIDATE GENE ANALYSIS3. CANDIDATE GENE ANALYSIS4. CYTOGENETIC ANALYSIS4. CYTOGENETIC ANALYSIS

LINKAGE STUDIESLINKAGE STUDIES

PARAMETRIC LINKAGE STUDIESPARAMETRIC LINKAGE STUDIES

NONPARAMETRIC LINKAGE STUDIESNONPARAMETRIC LINKAGE STUDIES

• ALSO KNOWN AS THE AFFECTED SIBLING PAIR ALSO KNOWN AS THE AFFECTED SIBLING PAIR (ASP) METHOD(ASP) METHOD

• IN THIS DISORDER, THE FREQUENCY WITH WHICH IN THIS DISORDER, THE FREQUENCY WITH WHICH THE GIVEN GENETIC MARKER IS INHERITED FROM A THE GIVEN GENETIC MARKER IS INHERITED FROM A PARENT IS MEASURED.PARENT IS MEASURED.

• IF THIS FREQUENCY EXCEEDS 50% IN AFFECTED IF THIS FREQUENCY EXCEEDS 50% IN AFFECTED PAIRS OF SIBLINGS, LINKAGE IS LIKELY (I.E. THE PAIRS OF SIBLINGS, LINKAGE IS LIKELY (I.E. THE DISEASE GENE AND THE INHERITED MARKER ARE DISEASE GENE AND THE INHERITED MARKER ARE IN LINKAGE.)IN LINKAGE.)

ASSOCIATION STUDIESASSOCIATION STUDIES

• SIMPLER THAN LINKAGE STUDIES.SIMPLER THAN LINKAGE STUDIES.• IN THIS METHOD, THE FREQUENCY OF MARKERS IS COMPARED IN IN THIS METHOD, THE FREQUENCY OF MARKERS IS COMPARED IN

AFFECTED AND UNAFFECTED SUBJECTS.AFFECTED AND UNAFFECTED SUBJECTS.• A CHI-SQUARE TEST IS USED TO COMPARE FREQUENCIES OF THE A CHI-SQUARE TEST IS USED TO COMPARE FREQUENCIES OF THE

MARKER IN BOTH GROUPS, AND THE RELATIVE RISK CAN BE MARKER IN BOTH GROUPS, AND THE RELATIVE RISK CAN BE CALCULATED.CALCULATED.

• IN SUCH STUDIES, POPULATIONS MUST IDEALLY BE AS GENETICALLY IN SUCH STUDIES, POPULATIONS MUST IDEALLY BE AS GENETICALLY HOMOGENEOUS AS POSSIBLE.HOMOGENEOUS AS POSSIBLE.

HOW DO WE FIND THE GENES ONCE HOW DO WE FIND THE GENES ONCE LINKAGE IS ESTABLISHED?LINKAGE IS ESTABLISHED?

• USE A CANDIDATE APPROACH – THAT IS, CONCENTRATE ON THOSE USE A CANDIDATE APPROACH – THAT IS, CONCENTRATE ON THOSE MARKERS CLOSE TO GENES THAT MAY BE RELEVANT.MARKERS CLOSE TO GENES THAT MAY BE RELEVANT.

• IF THESE ARE NOT KNOWN, SYSTEMATICALLY SEARCH THE REGION IF THESE ARE NOT KNOWN, SYSTEMATICALLY SEARCH THE REGION CLOSE TO THE MARKER.CLOSE TO THE MARKER.

• IDEALLY, AN ENTIRE GENOME SCAN FOR LINKAGE DISEQUILIBRIUM IDEALLY, AN ENTIRE GENOME SCAN FOR LINKAGE DISEQUILIBRIUM SHOULD BE DONE – THIS IS TIME-CONSUMING, BUT MODERN SHOULD BE DONE – THIS IS TIME-CONSUMING, BUT MODERN TECHNOLOGIES HELP.TECHNOLOGIES HELP.

CANDIDATE GENE STUDIESCANDIDATE GENE STUDIES

IN THESE STUDIES, GENES THAT CODE FOR PROTEINS BELIEVED TO IN THESE STUDIES, GENES THAT CODE FOR PROTEINS BELIEVED TO BE IMPORTANT IN A GIVEN DISORDER ARE STUDIED IN AFFECTED BE IMPORTANT IN A GIVEN DISORDER ARE STUDIED IN AFFECTED AND UNAFFECTED PATIENTS.AND UNAFFECTED PATIENTS.

SINCE THE PATHOPHYSIOLOGY OF PSYCHIATRIC ILLNESS IS NOT SINCE THE PATHOPHYSIOLOGY OF PSYCHIATRIC ILLNESS IS NOT GENERALLY KNOWN, THESE GENES HAVE TO BE “GUESSED AT” - E.G GENERALLY KNOWN, THESE GENES HAVE TO BE “GUESSED AT” - E.G DOPAMINE RECEPTORS IN SCHIZOPHRENIA.DOPAMINE RECEPTORS IN SCHIZOPHRENIA.

COMPARING FREQUENCIES OF DIFFERENT GENE COMPARING FREQUENCIES OF DIFFERENT GENE POLYMORPHISMS MAY SHOW ASSOCIATIONS BETWEEN A POLYMORPHISMS MAY SHOW ASSOCIATIONS BETWEEN A GENE AND A GIVEN DISORDERGENE AND A GIVEN DISORDER..

IF ONE POLYMORPHISM IS MORE THEN SUSPECT A CANDIDATE.IF ONE POLYMORPHISM IS MORE THEN SUSPECT A CANDIDATE.

CYTOGENETIC STUDIESCYTOGENETIC STUDIES

• THESE ARE USED WHEN DISORDERS IN CHROMOSOME NUMBER OR THESE ARE USED WHEN DISORDERS IN CHROMOSOME NUMBER OR STRUCTURE ARE SUSPECTED.STRUCTURE ARE SUSPECTED.

• THEY ARE MORE USEFUL IN STUDYING THEY ARE MORE USEFUL IN STUDYING INHERITED INHERITED NEUROPSYCHIATRIC SYNDROMES NEUROPSYCHIATRIC SYNDROMES WHERE ANEUPLOIDY OR WHERE ANEUPLOIDY OR STRUCTURAL DEFICITS ARE DIAGNOSTICSTRUCTURAL DEFICITS ARE DIAGNOSTIC

• EXAMPLES: DOWN'S SYNDROME, TURNER'S SYNDROME, FRAGILE X EXAMPLES: DOWN'S SYNDROME, TURNER'S SYNDROME, FRAGILE X SYNDROMESYNDROME

FINDINGS IN COMMON DISORDERSFINDINGS IN COMMON DISORDERS

• SCHIZOPHRENIASCHIZOPHRENIA• BIPOLAR DISORDERBIPOLAR DISORDER• DEPRESSIONDEPRESSION• OCDOCD• PANIC DISORDERPANIC DISORDER• ALCOHOL DEPENDENCE SYNDROMEALCOHOL DEPENDENCE SYNDROME

GENETIC CONTRIBUTIONS ACROSS GENETIC CONTRIBUTIONS ACROSS DISORDERSDISORDERS

(MERIKANGAS AND RISCH, 2003)(MERIKANGAS AND RISCH, 2003)

HERITABILITY ESTIMATES FOR COMMON HERITABILITY ESTIMATES FOR COMMON DISORDERSDISORDERS

(HILL AND SAHHAR, 2006)(HILL AND SAHHAR, 2006)

SCHIZOPHRENIASCHIZOPHRENIA

SCHIZOPHRENIASCHIZOPHRENIA• FAMILY STUDIES HAVE FOUND HIGH ODDS RATIOS FOR AFFECTED FAMILY STUDIES HAVE FOUND HIGH ODDS RATIOS FOR AFFECTED

RELATIVES, UP TO 9-14.RELATIVES, UP TO 9-14.• RATES ARE HIGHER IN FIRST THAN IN SECOND DEGREE RELATIVES, AND RATES ARE HIGHER IN FIRST THAN IN SECOND DEGREE RELATIVES, AND

APPROACH POPULATION RATES FOR THIRD DEGREE RELATIVES.APPROACH POPULATION RATES FOR THIRD DEGREE RELATIVES.• FAMILIALITY SEEMS TO BE STRONGER IN THE CASE OF EARLY ONSET FAMILIALITY SEEMS TO BE STRONGER IN THE CASE OF EARLY ONSET

SCHIZOPHRENIA (DEFINED AS <25 YEARS IN GENETIC STUDIES)SCHIZOPHRENIA (DEFINED AS <25 YEARS IN GENETIC STUDIES)• CONCORDANCE FOR MONOZYGOTIC TWINS IS 47-53%, AS OPPOSED TO CONCORDANCE FOR MONOZYGOTIC TWINS IS 47-53%, AS OPPOSED TO

AROUND 4-15% FOR DIZYGOTIC TWINSAROUND 4-15% FOR DIZYGOTIC TWINS• RISK OF SCHIZOPHRENIA IN THE OFFSPRING OF UNAFFECTED TWINS IS RISK OF SCHIZOPHRENIA IN THE OFFSPRING OF UNAFFECTED TWINS IS

EQUAL TO THAT IN THE OFFSPRING OF AFFECTED TWINS.EQUAL TO THAT IN THE OFFSPRING OF AFFECTED TWINS.• RATES OF SCHIZOAFFECTIVE DISORDER AND OTHER NONAFFECTIVE RATES OF SCHIZOAFFECTIVE DISORDER AND OTHER NONAFFECTIVE

PSYCHOSES ARE ALSO HIGHER IN TWINS.PSYCHOSES ARE ALSO HIGHER IN TWINS.

SCHIZOPHRENIASCHIZOPHRENIA

• ADOPTION STUDIES HAVE SHOWN CLOSER CONCORDANCE FOR ADOPTION STUDIES HAVE SHOWN CLOSER CONCORDANCE FOR BIOLOGICAL THAN ADOPTIVE PARENTS AND RELATIVES.BIOLOGICAL THAN ADOPTIVE PARENTS AND RELATIVES.

• THERE IS SOME EVIDENCE FOR SHARED GENETIC LIABILITY TO THERE IS SOME EVIDENCE FOR SHARED GENETIC LIABILITY TO SCHIZOPHRENIA AND BIPOLAR DISORDER (COMMON LINKAGES AT SCHIZOPHRENIA AND BIPOLAR DISORDER (COMMON LINKAGES AT 6Q, 10Q, 13Q AND 22Q)6Q, 10Q, 13Q AND 22Q)

• THERE IS ALSO A LINK WITH PSYCHOTIC MOOD DISORDERS AND THERE IS ALSO A LINK WITH PSYCHOTIC MOOD DISORDERS AND PERSONALITY DISORDERS, ESPECIALLY CLUSTER A PERSONALITY.PERSONALITY DISORDERS, ESPECIALLY CLUSTER A PERSONALITY.

GENES IMPLICATED IN SCHIZOPHRENIAGENES IMPLICATED IN SCHIZOPHRENIA• CATECHOL O-METHYL TRANSFERASE (COMT) – 22QCATECHOL O-METHYL TRANSFERASE (COMT) – 22Q• PROLINE DEHYDROGENASE (PRODH) – 22QPROLINE DEHYDROGENASE (PRODH) – 22Q• NEUREGULIN (NRG1) – 8PNEUREGULIN (NRG1) – 8P• CALCINEURIN A GAMMA (PPP3CC) – 8PCALCINEURIN A GAMMA (PPP3CC) – 8P• DYSTROBREVIN BINDING PROTEIN – 6PDYSTROBREVIN BINDING PROTEIN – 6P• DAAO AND G72 – EPISTASIS – 13QDAAO AND G72 – EPISTASIS – 13Q• CHOLINERGIC ALPHA-7 RECEPTOR – 15QCHOLINERGIC ALPHA-7 RECEPTOR – 15Q• DOPAMINE BETA-HYDROXYLASE AND NMDA RECEPTOR SUBUNIT - DOPAMINE BETA-HYDROXYLASE AND NMDA RECEPTOR SUBUNIT -

9Q9Q• DISC GENEDISC GENE

BIPOLAR DISORDERBIPOLAR DISORDER

• FAMILY STUDIES FIND AN ODDS RATIO OF 5-10 FOR FIRST-DEGREE FAMILY STUDIES FIND AN ODDS RATIO OF 5-10 FOR FIRST-DEGREE RELATIVES.RELATIVES.

• THIS EFFECT IS STRONGER FOR EARLY-ONSET BIPOLAR DISORDER.THIS EFFECT IS STRONGER FOR EARLY-ONSET BIPOLAR DISORDER.• MONOZYGOTIC TWIN CONCORDANCE IS 67%, AND DIZYGOTIC TWIN MONOZYGOTIC TWIN CONCORDANCE IS 67%, AND DIZYGOTIC TWIN

CONCORDANCE IS 20%CONCORDANCE IS 20%• TWO ADOPTION STUDIES FOUND HIGHER RATES IN BIOLOGICAL PARENTS, TWO ADOPTION STUDIES FOUND HIGHER RATES IN BIOLOGICAL PARENTS,

AND NORMAL RATES IN ADOPTIVE PARENTS.AND NORMAL RATES IN ADOPTIVE PARENTS.• LINK TO UNIPOLAR DEPRESSION IN ONE DIRECTION – BIPOLAR PROBANDS LINK TO UNIPOLAR DEPRESSION IN ONE DIRECTION – BIPOLAR PROBANDS

HAVE MORE RELATIVES WITH UNIPOLAR DISORDER, BUT NOT VICE VERSA.HAVE MORE RELATIVES WITH UNIPOLAR DISORDER, BUT NOT VICE VERSA.• SIGNIFICANT ASSOCIATION WITH SUBSTANCE USE DISORDERS AND SIGNIFICANT ASSOCIATION WITH SUBSTANCE USE DISORDERS AND

CONDUCT DISORDERS IN FAMILY STUDIES.CONDUCT DISORDERS IN FAMILY STUDIES.• LINKAGE WITH SCHIZOPHRENIA / SCHIZOAFFECTIVE AS DISCUSSED ABOVE.LINKAGE WITH SCHIZOPHRENIA / SCHIZOAFFECTIVE AS DISCUSSED ABOVE.

GENES IN BIPOLAR DISORDERGENES IN BIPOLAR DISORDER

• BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) – BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) – 11P11P

• G-PROTEIN RECEPTOR KINASE (GSK-3) – 22QG-PROTEIN RECEPTOR KINASE (GSK-3) – 22Q• G72 (MODULATES NMDA RECEPTORS) – 13QG72 (MODULATES NMDA RECEPTORS) – 13Q• OTHERS – GSK-3 BETA, CLOCK GENESOTHERS – GSK-3 BETA, CLOCK GENES

DEPRESSIONDEPRESSION

DEPRESSIONDEPRESSION

• WINOKUR PROPOSED THE CONCEPT OF THE DEPRESSIVE WINOKUR PROPOSED THE CONCEPT OF THE DEPRESSIVE SPECTRUM, INCLUDING ALCOHOLISM, ANTISOCIAL BEHAVIOUR SPECTRUM, INCLUDING ALCOHOLISM, ANTISOCIAL BEHAVIOUR AND SOMATIZATION / CONVERSION.AND SOMATIZATION / CONVERSION.

• ON THE WHOLE, THE HERITABILITY OF DEPRESSION IS LOWER ON THE WHOLE, THE HERITABILITY OF DEPRESSION IS LOWER THAN THAT OF BPAD.THAN THAT OF BPAD.

• BPAD PROBANDS HAVE MORE RELATIVES WITH UNIPOLAR BPAD PROBANDS HAVE MORE RELATIVES WITH UNIPOLAR DEPRESSION THAN CONTROLS.DEPRESSION THAN CONTROLS.

GENES IN DEPRESSIONGENES IN DEPRESSION

• FEW IDENTIFIED:FEW IDENTIFIED:

1. BDNF ON 11P1. BDNF ON 11P2. CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN (CREB) 2. CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN (CREB) ON CHROMOSOME 2ON CHROMOSOME 23. SEROTONIN TRANSPORTER (5HTT) POLYMORPHISM - 17Q3. SEROTONIN TRANSPORTER (5HTT) POLYMORPHISM - 17Q4. MONOAMINE OXIDASE A - XP4. MONOAMINE OXIDASE A - XP

OCDOCD

PANIC DISORDERPANIC DISORDER

• FAMILIARITY SHOWN IN FAMILY STUDIES, MORE IN THE CASE OF FAMILIARITY SHOWN IN FAMILY STUDIES, MORE IN THE CASE OF FEMALE RELATIVESFEMALE RELATIVES..

• SOME GENETIC OVERLAP WITH GENERALIZED ANXIETY DISORDER SOME GENETIC OVERLAP WITH GENERALIZED ANXIETY DISORDER AND MAJOR DEPRESSION.AND MAJOR DEPRESSION.

• 2-3 FOLD HIGHER CONCORDANCE IN MONOZYGOTIC TWINS 2-3 FOLD HIGHER CONCORDANCE IN MONOZYGOTIC TWINS COMPARED TO DIZYGOTIC TWINSCOMPARED TO DIZYGOTIC TWINS

• SIGNIFICANT OVERLAP WITH ALCOHOL DEPENDENCE IN FIRST-SIGNIFICANT OVERLAP WITH ALCOHOL DEPENDENCE IN FIRST-DEGREE RELATIVES, MORE SO IN WOMEN WITH PANIC DISORDER.DEGREE RELATIVES, MORE SO IN WOMEN WITH PANIC DISORDER.

ALCOHOLISMALCOHOLISM

• EARLY-ONSET ALCOHOLISM (<25 YEARS, TYPE II)EARLY-ONSET ALCOHOLISM (<25 YEARS, TYPE II) HAS A STRONG GENETIC HAS A STRONG GENETIC COMPONENT.COMPONENT.

• ASSOCIATION WITH EXTERNALIZING DISORDERS AND ADULT ANTISOCIAL BEHAVIOUR.ASSOCIATION WITH EXTERNALIZING DISORDERS AND ADULT ANTISOCIAL BEHAVIOUR.• ASSOCIATION WITH MOOD DISORDERS, BOTH UNIPOLAR AND BIPOLAR.ASSOCIATION WITH MOOD DISORDERS, BOTH UNIPOLAR AND BIPOLAR.• TWIN AND ADOPTION STUDIES SUPPORT A GENETIC AETIOLOGY FOR ALCOHOLISM, TWIN AND ADOPTION STUDIES SUPPORT A GENETIC AETIOLOGY FOR ALCOHOLISM,

ESPECIALLY IN MEN.ESPECIALLY IN MEN.• THERE MAY BE AN INTERACTION BETWEEN GENOTYPE AND GENDER – WOMEN REQUIRE THERE MAY BE AN INTERACTION BETWEEN GENOTYPE AND GENDER – WOMEN REQUIRE

MORE LOADINGMORE LOADING• POLYGENIC MODELS HAVE THE BEST SUPPORT.POLYGENIC MODELS HAVE THE BEST SUPPORT.• LINKAGE TO CHROMOSOMES 1, 7 AND 2.LINKAGE TO CHROMOSOMES 1, 7 AND 2.• POSSIBLE PROTECTIVE EFFECT OF ALCOHOL DEHYDROGENASE ON CHROMOSOME 4POSSIBLE PROTECTIVE EFFECT OF ALCOHOL DEHYDROGENASE ON CHROMOSOME 4• SEROTONIN, GABA-A AND DOPAMINE RECEPTOR GENES ALSO IMPLICATEDSEROTONIN, GABA-A AND DOPAMINE RECEPTOR GENES ALSO IMPLICATED

LIMITATIONS OF GENETIC STUDIES IN LIMITATIONS OF GENETIC STUDIES IN PSYCHIATRYPSYCHIATRY

• DIAGNOSES ARE HETEROGENOUS, AND DO NOT MATCH TO CLEAR DIAGNOSES ARE HETEROGENOUS, AND DO NOT MATCH TO CLEAR PHENOTYPESPHENOTYPES

• RELIABILITY / VALIDITY IN IDENTIFYING CASESRELIABILITY / VALIDITY IN IDENTIFYING CASES• THE PROBLEM OF “BROAD DEFINITIONS”THE PROBLEM OF “BROAD DEFINITIONS”• GENETIC HETEROGENEITY AND PHENOCOPIESGENETIC HETEROGENEITY AND PHENOCOPIES• SIMPLIFYING ASSUMPTIONSSIMPLIFYING ASSUMPTIONS• EFFECT OF POPULATION INTERBREEDING, MIGRATIONEFFECT OF POPULATION INTERBREEDING, MIGRATION• METHODOLOGICAL ISSUES AND FLAWSMETHODOLOGICAL ISSUES AND FLAWS• COMPLEX GENETICS – NOT FITTING INTO SIMPLE MODELSCOMPLEX GENETICS – NOT FITTING INTO SIMPLE MODELS• GENETIC PLEIOTROPY – ONE GENE MANIFESTING IN DIFFERENT WAYSGENETIC PLEIOTROPY – ONE GENE MANIFESTING IN DIFFERENT WAYS• OTHER EFFECTS, SUCH AS EPIGENETIC MODIFICATIONOTHER EFFECTS, SUCH AS EPIGENETIC MODIFICATION• STATISTICAL ERRORS DUE TO MULTIPLE COMPARISONSSTATISTICAL ERRORS DUE TO MULTIPLE COMPARISONS

PHENOCOPIESPHENOCOPIES

PERVASIVEHYPERACTIVITY

(phenotype)

ADHD

Conduct disorder

Anxiety disorder

Learning disability

Developmental disorders

Abuse and PTSD

OVERCOMING HURDLESOVERCOMING HURDLES

• ONE WAY OF AVOIDING THESE PROBLEMS IS IN IDENTIFYING A ONE WAY OF AVOIDING THESE PROBLEMS IS IN IDENTIFYING A “PURER” AND MORE VALID AND RELIABLE PHENOTYPE.“PURER” AND MORE VALID AND RELIABLE PHENOTYPE.

• IDEALLY, IT SHOULD BE MEASURABLE BY A LABORATORY TEST OR IDEALLY, IT SHOULD BE MEASURABLE BY A LABORATORY TEST OR OTHER OBJECTIVE PROCEDURE.OTHER OBJECTIVE PROCEDURE.

• THIS “INTERMEDIATE PHENOTYPE” APPROACH GAVE RISE TO THE THIS “INTERMEDIATE PHENOTYPE” APPROACH GAVE RISE TO THE CONCEPT OF CONCEPT OF ENDOPHENOTYPES.ENDOPHENOTYPES.

ENDOPHENOTYPESENDOPHENOTYPES

• COINED BY BERNARD JOHN AND KENNETH R. LEWIS IN A 1966 PAPER ATTEMPTING TO EXPLAIN THE GEOGRAPHIC DISTRIBUTION OF GRASSHOPPERS

• ENDOPHENOTYPES ARE “INTERNAL PHENOTYPES” DISCOVERABLE ENDOPHENOTYPES ARE “INTERNAL PHENOTYPES” DISCOVERABLE BY A LABORATORY TEST.BY A LABORATORY TEST.

• THEY INTERACT WITH ENVIRONMENTAL FACTORS TO PRODUCE A THEY INTERACT WITH ENVIRONMENTAL FACTORS TO PRODUCE A COMPLEX PHENOTYPE, OR DISORDER.COMPLEX PHENOTYPE, OR DISORDER.

• BECAUSE OF THEIR GREATER SIMPLICITY, VALIDITY AND BECAUSE OF THEIR GREATER SIMPLICITY, VALIDITY AND RELIABILITY, IT IS EASIER TO STUDY THEM IN FAMILIES AND RELIABILITY, IT IS EASIER TO STUDY THEM IN FAMILIES AND ASSOCIATE THEM WITH CANDIDATE GENES.ASSOCIATE THEM WITH CANDIDATE GENES.

CRITERIA FOR AN ENDOPHENOTYPE CRITERIA FOR AN ENDOPHENOTYPE (GOTTESMAN AND SHIELDS, 2003)(GOTTESMAN AND SHIELDS, 2003)

• AN ENDOPHENOTYPE MUST SEGREGATE WITH ILLNESS IN THE POPULATION.

• AN ENDOPHENOTYPE MUST BE HERITABLE.• AN ENDOPHENOTYPE MUST BE STATE-INDEPENDENT (I.E., MANIFESTS

WHETHER ILLNESS IS ACTIVE OR IN REMISSION).• AN ENDOPHENOTYPE MUST CO-SEGREGATE WITH ILLNESS WITHIN

FAMILIES.• AN ENDOPHENOTYPE MUST BE PRESENT AT A HIGHER RATE WITHIN

AFFECTED FAMILIES THAN IN THE POPULATION.• AN ENDOPHENOTYPE MUST BE AMENABLE TO RELIABLE

MEASUREMENT, AND BE SPECIFIC TO THE ILLNESS OF INTEREST.

TYPES OF ENDOPHENOTYPETYPES OF ENDOPHENOTYPE

• STRUCTURAL ANATOMICALSTRUCTURAL ANATOMICAL• FUNCTIONAL NEUROANATOMICALFUNCTIONAL NEUROANATOMICAL• PHYSICAL FINDINGPHYSICAL FINDING• BIOCHEMICALBIOCHEMICAL• NEUROENDOCRINENEUROENDOCRINE• NEUROPSYCHOLOGICALNEUROPSYCHOLOGICAL

EXAMPLES OF ENDOPHENOTYPESEXAMPLES OF ENDOPHENOTYPES

• SENSORY GATING ANOMALIES IN SCHIZOPHRENIA.SENSORY GATING ANOMALIES IN SCHIZOPHRENIA.

• EYE TRACKING ABNORMALITIES IN SCHIZOPHRENIA.EYE TRACKING ABNORMALITIES IN SCHIZOPHRENIA.

• NEUROPSYCHOLOGICAL DEFICITS IN BIPOLAR DISORDER, NEUROPSYCHOLOGICAL DEFICITS IN BIPOLAR DISORDER, SCHIZOPHRENIA AND POSSIBLY OCD.SCHIZOPHRENIA AND POSSIBLY OCD.

PHARMACOGENETICS AND PHARMACOGENETICS AND PHARMACOGENOMICSPHARMACOGENOMICS

• PHARMACOGENETICS IS THE STUDY OF INHERITED GENETIC DIFFERENCES IN DRUG METABOLIC PATHWAYS WHICH CAN AFFECT INDIVIDUAL RESPONSES TO DRUGS, BOTH IN TERMS OF THERAPEUTIC EFFECT AS WELL AS ADVERSE EFFECTS. (KLOTZ, 2007)

• PHARMACOGENOMICS IS THE STUDY OF THE ROLE OF GENETICS IN DRUG RESPONSE. IT DEALS WITH THE INFLUENCE OF ACQUIRED AND INHERITED GENETIC VARIATION ON DRUG RESPONSE IN PATIENTS BY CORRELATING GENE EXPRESSION OR SINGLE-NUCLEOTIDE POLYMORPHISMS WITH DRUG ABSORPTION, DISTRIBUTION, METABOLISM AND ELIMINATION, AS WELL AS DRUG RECEPTOR TARGET EFFECTS. (JOHNSON, 2003)

• PHARMACOGENETICS FOCUSES ON SINGLE DRUG-GENE INTERACTIONS, WHILE PHARMACOGENOMICS ENCOMPASSES A MORE GENOME-WIDE ASSOCIATION APPROACH, INCORPORATING GENOMICS AND EPIGENETICS WHILE DEALING WITH THE EFFECTS OF MULTIPLE GENES ON DRUG RESPONSE

PHARMACOGENETICS AND PHARMACOGENETICS AND PHARMACOGENOMICSPHARMACOGENOMICS

• THOUGH EFFECTIVE DRUGS EXIST FOR MANY PSYCHIATRIC DISORDERS, THEY ARE THOUGH EFFECTIVE DRUGS EXIST FOR MANY PSYCHIATRIC DISORDERS, THEY ARE NOT CURATIVE.NOT CURATIVE.

• THEIR EXACT MECHANISMS OF ACTION ARE UNCLEAR.THEIR EXACT MECHANISMS OF ACTION ARE UNCLEAR.• RESPONSE RATES ARE GENERALLY AROUND 50-60%.RESPONSE RATES ARE GENERALLY AROUND 50-60%.• ATTEMPTS TO PREDICT RESPONSE BASED ON CLINICAL PARAMETERS ARE NOT ATTEMPTS TO PREDICT RESPONSE BASED ON CLINICAL PARAMETERS ARE NOT

ALWAYS SUCCESSFUL.ALWAYS SUCCESSFUL.• INITIALLY, ATTENTION WAS DEVOTED TO IDENTIFYING GENETIC DIFFERENCES IN INITIALLY, ATTENTION WAS DEVOTED TO IDENTIFYING GENETIC DIFFERENCES IN

DRUG METABOLISM.DRUG METABOLISM.• LATER, THIS GENERALIZED TO FINDING GENES THAT COULD BE ASSOCIATED WITH LATER, THIS GENERALIZED TO FINDING GENES THAT COULD BE ASSOCIATED WITH

DRUG RESPONSE, OR WITH SPECIFIC ADVERSE EFFECTS.DRUG RESPONSE, OR WITH SPECIFIC ADVERSE EFFECTS.• THE LATEST ADVANCE HAS BEEN GENOME SCANNING TO IDENTIFY THE EFFECTS OF THE LATEST ADVANCE HAS BEEN GENOME SCANNING TO IDENTIFY THE EFFECTS OF

DRUGS ON GENE EXPRESSION AND PROTEIN SYNTHESISDRUGS ON GENE EXPRESSION AND PROTEIN SYNTHESIS

EXAMPLES OF EXAMPLES OF PHARMACOGENETIC/GENOMIC FINDINGS:PHARMACOGENETIC/GENOMIC FINDINGS:

GENETIC COUNSELINGGENETIC COUNSELING

REFERENCESREFERENCES• GRAFEN, ALAN; RIDLEY, MARK (2006). RICHARD DAWKINS: HOW A SCIENTIST CHANGED THE WAY WE THINK. NEW YORK, NEW YORK: OXFORD GRAFEN, ALAN; RIDLEY, MARK (2006). RICHARD DAWKINS: HOW A SCIENTIST CHANGED THE WAY WE THINK. NEW YORK, NEW YORK: OXFORD

UNIVERSITY PRESS. P. 69. ISBN 0-19-929116-0.UNIVERSITY PRESS. P. 69. ISBN 0-19-929116-0.

• WIO, S. HORACIO, DEZA, R. ROBERTO & LOPEZ, M. JUAN (2012). AN INTRODUCTION TO STOCHASTIC PROCESSES AND NONEQUILIBRIUM WIO, S. HORACIO, DEZA, R. ROBERTO & LOPEZ, M. JUAN (2012). AN INTRODUCTION TO STOCHASTIC PROCESSES AND NONEQUILIBRIUM STATISTICAL PHYSICS. WORLD SCIENTIFIC PUBLISHING. ISBN 978-981-4374-78-1.STATISTICAL PHYSICS. WORLD SCIENTIFIC PUBLISHING. ISBN 978-981-4374-78-1.

• THE ORIGIN OF SCHIZOPHRENIA: GENETIC THESIS, EPIGENETIC ANTITHESIS, AND RESOLVING SYNTHESIS.ARTURAS PETRONIS. BIOL THE ORIGIN OF SCHIZOPHRENIA: GENETIC THESIS, EPIGENETIC ANTITHESIS, AND RESOLVING SYNTHESIS.ARTURAS PETRONIS. BIOL PSYCHIATRY. 2004 MAY 15; 55(10): 965–970. DOI: 10.1016/J.BIOPSYCH.2004.02.005PSYCHIATRY. 2004 MAY 15; 55(10): 965–970. DOI: 10.1016/J.BIOPSYCH.2004.02.005

• BURMEISTER M, MCINNIS MG, ZÖLLNER S (2008). "PSYCHIATRIC GENETICS: PROGRESS AMID CONTROVERSY". NAT REV GENET 9 (7): 527–40. BURMEISTER M, MCINNIS MG, ZÖLLNER S (2008). "PSYCHIATRIC GENETICS: PROGRESS AMID CONTROVERSY". NAT REV GENET 9 (7): 527–40. DOI:10.1038/NRG2381. PMID 18560438.DOI:10.1038/NRG2381. PMID 18560438.

• GOTTESMAN II, GOULD TD (APRIL 2003). "THE ENDOPHENOTYPE CONCEPT IN PSYCHIATRY: ETYMOLOGY AND STRATEGIC INTENTIONS". AM J GOTTESMAN II, GOULD TD (APRIL 2003). "THE ENDOPHENOTYPE CONCEPT IN PSYCHIATRY: ETYMOLOGY AND STRATEGIC INTENTIONS". AM J PSYCHIATRY 160 (4): 636–45. DOI:10.1176/APPI.AJP.160.4.636. PMID 12668349.PSYCHIATRY 160 (4): 636–45. DOI:10.1176/APPI.AJP.160.4.636. PMID 12668349.

• KLOTZ, U. (2007). "THE ROLE OF PHARMACOGENETICS IN THE METABOLISM OF ANTIEPILEPTIC DRUGS: PHARMACOKINETIC AND THERAPEUTIC KLOTZ, U. (2007). "THE ROLE OF PHARMACOGENETICS IN THE METABOLISM OF ANTIEPILEPTIC DRUGS: PHARMACOKINETIC AND THERAPEUTIC IMPLICATIONS.". CLIN PHARMACOKINET 46 (4): 271–9. DOI:10.2165/00003088-200746040-00001. PMID 17375979.IMPLICATIONS.". CLIN PHARMACOKINET 46 (4): 271–9. DOI:10.2165/00003088-200746040-00001. PMID 17375979.

• JOHNSON JA (NOVEMBER 2003). "PHARMACOGENETICS: POTENTIAL FOR INDIVIDUALIZED DRUG THERAPY THROUGH GENETICS.". TRENDS JOHNSON JA (NOVEMBER 2003). "PHARMACOGENETICS: POTENTIAL FOR INDIVIDUALIZED DRUG THERAPY THROUGH GENETICS.". TRENDS GENET 19 (11): 660–6. DOI:10.1016/J.TIG.2003.09.008. PMID 14585618.GENET 19 (11): 660–6. DOI:10.1016/J.TIG.2003.09.008. PMID 14585618.

• HTTP://WWW.NSGC.ORG/ABOUT/FAQSDEFINITIONS/TABID/97/DEFAULT.ASPXHTTP://WWW.NSGC.ORG/ABOUT/FAQSDEFINITIONS/TABID/97/DEFAULT.ASPX

THANK YOUTHANK YOU