06 Genetics

8/9/2019 06 Genetics

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The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC,

Gabbard GO. 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org1

Slide show includes

Topic Headings

Tables and Figures

Key Points

GeneticsPrabhakara V. Choudary, Ph.D., F.R.S.C.,

James A. Knowles, M.D., Ph.D.

The American Psychiatric Publishing

TEXTBOOK OF PSYCHIATRYFifth EditionEdited by Robert E. Hales, M.D., M.B.A., Stuart C. Yudofsky, M.D., Glen O. Gabbard, M.D.

2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org

CHAPTER 6


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CHAPTER 6 Topic Headings

PSYCHIATRIC GENETICS: AIMS AND METHODS

AimsMethods

Is the Illness Familial?Family Risk Studies and

Epidemiological Studies

Do Genetic Factors Contribute to the Illness?

Twin and Adoption Studies

What Are the Various Clinical Expressions of the

Abnormal Gene(s)?Spectrum Studies

What Are the Early Manifestations of andEnvironmental Risk Factors for the Illness?

High-Risk StudiesWhat Is the Mode ofTransmission?

Segregation Analysis

Where Is the Abnormal Gene?Genetic Linkage

Analysis and Association Studies

PROBLEMS OF DIAGNOSIS AND CLASSIFICATION

IN GENETIC INVESTIGATIONS

GENETICS OF PSYCHIATRIC DISORDERS

Schizophrenia

Family Studies

Twin StudiesAdoption Studies

High-Risk Studies

Mode of Inheritance

Linkage, Association, and Gene Expression Analyses

Mood (Affective) Disorders

Genetic Association Studies of DepressionOther Approaches

Anxiety Disorders

Panic Disorder

Obsessive-Compulsive Disorder

Other Anxiety Disorders (Generalized Anxiety Disorder,

Phobias, Posttraumatic Stress Disorder)

Drug Dependence

Suicide and Impulsive BehaviorNeuropsychiatric Disorders

EPIGENETICSNOSOLOGY

GENETIC COUNSELING

PSYCHOPHARMACOGENETICS

PREVENTION AND TREATMENT

CONCLUSION


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CHAPTER 6 Topic Headings

PSYCHIATRIC GENETICS: AIMS AND METHODS

Aims

MethodsIs the Illness Familial?Family Risk Studies

and Epidemiological Studies

Do Genetic Factors Contribute to the Illness?

Twin and Adoption Studies

What Are the Various Clinical Expressions of

the Abnormal Gene(s)?Spectrum Studies

What Are the Early Manifestations of and

Environmental Risk Factors for the Illness?

High-Risk Studies

What Is the Mode ofTransmission? SegregationAnalysis

Where Is the Abnormal Gene? Genetic Linkage

Analysis and Association Studies

PROBLEMS OF DIAGNOSIS AND CLASSIFICATION

IN GENETIC INVESTIGATIONS

GENETICS OF PSYCHIATRIC DISORDERS

Schizophrenia

Family Studies

Twin StudiesAdoption Studies

High-Risk Studies

Mode of Inheritance

Linkage, Association, and Gene Expression

Analyses

Mood (Affective) Disorders

Genetic Association Studies of Depression

Other ApproachesAnxiety Disorders

Panic Disorder

Obsessive-Compulsive Disorder

Other Anxiety Disorders (Generalized Anxiety

Disorder, Phobias, Posttraumatic Stress

Disorder)

Drug Dependence

Suicide and Impulsive Behavior

Neuropsychiatric Disorders

EPIGENETICS

NOSOLOGY

GENETIC COUNSELING

PSYCHOPHARMACOGENETICS

PREVENTION AND TREATMENT

CONCLUSION


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CHAPTER 6 Tables and Figures

Table 61. Evidence in support of genetic transmission of various psychiatric disorders

Table 62. Relative risks for psychiatric disorders

Figure 61. Genetic linkage and recombination.

Figure 62. Schematic representation of a microsatellite marker.

Table 63. Candidate genes for schizophrenia

Table 64. National Institute of Mental Health Collaborative Study of Affective Disorders:

rates of illness in interviewed first-degree relatives

Table 65. Candidate genes for mood (affective) disorders

Summary Key Points


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TABLE 61. Evidence

in support of genetic

transmission of

various psychiatric

disorders

New research

methodologies and

techniques hold the

promise of determining

the location, nature, and

product of the geneticcontribution to many

illnesses. Table 61

presents a summary of

the research evidence in

support of genetic

transmission for various

psychiatric disorders.


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TABLE 62. Relative risks for psychiatric disorders

As seen in Table 62, which is based on selected methodologically sound studies, relative risk varies

from approximately 3 to 25 for the psychiatric disorders studied, indicating significant familial

aggregation for all of them. From these data, it appears that bipolar disorder, schizophrenia, panic

disorder, and alcoholism are familial disorders.


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FIGURE 61. Genetic linkage and

recombination.

Genetic linkage analysis is a technique based on exceptions to Mendels second law. This empirical

observation, also known as the law of independent assortment, states that alleles (specific gene

configurations) at different genetic loci are inherited independently of one another. This clearly applies

to loci lying on different chromosomes (Figure 61).

Depicted is a hypothetical family (circles: females;squares: males) transmitting an autosomal dominantdisease. The disease locus A (containing either the

defective allele a1 or its normal counterpart a2) liesclose to a marker locus B (containing marker alleles b

1and b2). The mother is affected with the disease(shaded symbol) and is heterozygous at both thedisease and the marker loci. The father is unaffected(open symbol) and is homozygous at both loci.Because the disease and marker loci are geneticallylinked (i.e., they lie near each other), crossing overrarely occurs between them. Most children who inheritthe disease allele a1 also receive the b1 marker allele

from their mother. Occasionally, a recombination event

(i.e., crossing over) occurs in the mother, and shetransfers a chromosome bearing the b2 marker allelealong with the disease allele (as occurred in thedaughter labeled recombinant). The frequency ofsuch recombinants increases as the distance betweenthe disease and marker locus increases.


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FIGURE 62. Schematic representation of a microsatellite marker.

Microsatellite markers have multiple alleles and therefore ensure that pedigree members are quite likely

to be heterozygous for the marker loci. As illustrated in Figure 62, individuals who are heterozygous at a

marker locus are essential for linkage studies. At the current microsatellite loci, 65%85% of the

individuals will be heterozygous. These markers are also densely and uniformly distributed in the human

genome, and genotypes for the pedigree members can be determined in a day or two using PCR.

Panel A. Autosomal homologous chromosome pairs from parents in a pedigree to be genotyped.Panel B. The DNA sequence on the long arm of the chromosome is examined in greater detail, revealing thevariable repeating DNA sequence termed a microsatellite marker. For a dinucleotide repeat, each boxrepresents two nucleotides (e.g., CA). Differing numbers of repeats of this dinucleotide are frequently found in

different individuals. The example shows a father with four and three repeats and a mother with five and tworepeats. (This is a simplification; most commonly there are 1520 repeats.)Panel C. Using DNA primers (* and **), one of which is radiolabeled, and a heat-stable DNA polymerase,repetitive cycles of DNA denaturation and replication exponentially amplify (105-fold) the DNA sequence bound

by the primers. This process is termed thepolymerase chain reaction (PCR) and is shown for only one of thetwo chromosomes of the father. Because the length of the fragment amplified is bounded by the primers, whichare attached to nonrepeating sequences outside the microsatellite region, the length of the product of thisreaction from each chromosome will be determined by the number of repeats.Panel D. The amplified DNA fragments are separated on the basis of size by gel electrophoresis.

Panel E.T

he presence of the bands is determined by autoradiography. Individuals have two bands thatcorrespond to the lengths of the amplified fragments. Each band is a marker for this region of the long arm of itsown chromosome. The inheritance of these fragments can then be followed through all members of a pedigreewhose DNA is available for the PCR reaction. Genotypes for each of the members of the hypothetical pedigreeare shown under the autoradiogram. If an autosomal dominant disease is depicted by solid symbols, allele 4

would be linked to the disorder in this pedigree. This linkage, if statistically significant, indicates that themicrosatellite marker is located close to the disease gene.

(continued)


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FIGURE 62. (continued)


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TABLE 63. Candidate genes for schizophrenia

Over the past decade, several genetic loci and candidate genes have been implicated in the

pathogenesis of schizophrenia, and some have been partially replicated. While none of these regions

has yet yielded a confirmed gene for schizophrenia, evidence is strong for several of them (Table 63).

(continued)


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The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC,Gabbard GO. 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org

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TABLE 63. (continued)


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TABLE 64. National Institute of Mental Health Collaborative Study of Affective Disorders:

rates of illness in interviewed first-degree relatives

The results of a very large NIMH collaborative study (2,226 interviewed relatives) that used the RDC for

interviewed relatives are summarized in Table 64. In addition to confirming the high rates of familial

incidence of mood disorders and a trend toward increased risk for those born in later versus earlier

decades of the twentieth century (i.e., an age-period-cohort effect), this study also found that first-

degree relatives of schizoaffective probands with depressive features had a somewhat elevated rate

(2.5%) of schizophrenia and a zero prevalence of bipolar I disorder. These findings, being quitedifferent from those for schizoaffective disorder of bipolar type, provided evidence that certain types

of schizoaffective disorder may not be related to bipolar disorder.

Source. Data from Andreasen et al. 1987.


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TABLE 65. Candidate genes for mood (affective) disorders

Microarray assays of postmortem brains have implicated a number of candidate genes and neurobiological

pathways in the etiology of major psychiatric disorders. Despite considerable divergence among the overall

findings reported by the studies, which can only be resolved by larger sample sizes and several more

studies, a trend is definitely emerging to build consensus on a few of the candidate genes, which are

summarized in Table 65.

(continued)


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TABLE 65. (continued)


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CHAPTER 6 Key Points

Multiple genes, each with a small effect, contribute to a psychiatric disease.

Environmental influences, interacting with genetic factors, have a definite rolein psychiatric illnesses.

None of the psychiatric diseases has a confirmed disease gene as yet, but

there are promising candidate genes for each disorder.

DISC1, NRG1, OLIG2, COMT, G72, APOL cluster, and SELENBP1 are

strong candidate genes for schizophrenia.

SLC6A4, BDNF, and NMDARare promising candidate genes for bipolarillness.

The fibroblast growth factor (FGF) system and GABA glutamate system

appear to be involved in genetic etiology of major depressive disorder.

Dysregulation of synaptic function, myelination, and oligodendrocyte function

seem to be common to several psychiatric disorders.

At the genetic level, bipolar disorder increasingly seems to share more

common features with schizophrenia than with major depressive disorder.

The HapMap project provides a bridge between linkage mapping and single

nucleotide polymorphisms (SNPs).

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Combining data on linkage, SNP association, regulation of gene expression,

and protein and RNA functions can be a powerful strategy for discoveringpsychiatric disease genes.

It remains to be seen whether blood/peripheral blood leukocytes (PBLs) can

serve as an alternative tissue that can be noninvasively accessed for routine

diagnosis of psychiatric illnesses.

Epigenetics likely has a greater role in the etiology of psychiatric illnesses

than is now apparent. It pays to play by the rules of ethics.

CHAPTER 6 Key Points (continued)

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