The American Psychiatric Publishing

TEXTBOOK OF PSYCHIATRY
Fifth Edition
Edited 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

Genetics
Prabhakara V. Choudary, Ph.D., F.R.S.C.,
James A. Knowles, M.D., Ph.D.

Slide show includes…

Topic Headings
Tables and Figures
Key Points

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 1
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
 CHAPTER 6 • Topic Headings

PSYCHIATRIC GENETICS: AIMS AND METHODS Mood (Affective) Disorders

Aims Genetic Association Studies of Depression
Methods Other Approaches
Is the Illness Familial?—Family Risk Studies and Anxiety Disorders
Epidemiological Studies Panic Disorder
Do Genetic Factors Contribute to the Illness? Obsessive-Compulsive Disorder
—Twin and Adoption Studies Other Anxiety Disorders (Generalized Anxiety Disorder,
What Are the Various Clinical Expressions of the Phobias, Posttraumatic Stress Disorder)
Abnormal Gene(s)?—Spectrum Studies Drug Dependence
What Are the Early Manifestations of and Suicide and Impulsive Behavior
Environmental Risk Factors for the Illness? Neuropsychiatric Disorders
—High-Risk Studies EPIGENETICS
What Is the Mode of Transmission?
NOSOLOGY
—Segregation Analysis
Where Is the Abnormal Gene?—Genetic Linkage GENETIC COUNSELING
Analysis and Association Studies PSYCHOPHARMACOGENETICS
PROBLEMS OF DIAGNOSIS AND CLASSIFICATION PREVENTION AND TREATMENT
IN GENETIC INVESTIGATIONS CONCLUSION
GENETICS OF PSYCHIATRIC DISORDERS
Schizophrenia
Family Studies
Twin Studies
Adoption Studies
High-Risk Studies
Mode of Inheritance
Linkage, Association, and Gene Expression Analyses

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 2
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
 CHAPTER 6 • Topic Headings
PSYCHIATRIC GENETICS: AIMS AND METHODS Mood (Affective) Disorders
Aims Genetic Association Studies of Depression
Methods Other Approaches
Is the Illness Familial?—Family Risk Studies Anxiety Disorders
and Epidemiological Studies Panic Disorder
Do Genetic Factors Contribute to the Illness? Obsessive-Compulsive Disorder
—Twin and Adoption Studies Other Anxiety Disorders (Generalized Anxiety
What Are the Various Clinical Expressions of Disorder, Phobias, Posttraumatic Stress
the Abnormal Gene(s)?—Spectrum Studies Disorder)
What Are the Early Manifestations of and Drug Dependence
Environmental Risk Factors for the Illness? Suicide and Impulsive Behavior
—High-Risk Studies Neuropsychiatric Disorders
What Is the Mode of Transmission? —Segregation
EPIGENETICS
Analysis
Where Is the Abnormal Gene? —Genetic Linkage NOSOLOGY
Analysis and Association Studies GENETIC COUNSELING
PROBLEMS OF DIAGNOSIS AND CLASSIFICATION PSYCHOPHARMACOGENETICS
IN GENETIC INVESTIGATIONS
PREVENTION AND TREATMENT
GENETICS OF PSYCHIATRIC DISORDERS
Schizophrenia CONCLUSION
Family Studies
Twin Studies
Adoption Studies
High-Risk Studies
Mode of Inheritance
Linkage, Association, and Gene Expression
Analyses

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 3
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
 CHAPTER 6 • Tables and Figures

Table 6–1. Evidence in support of genetic transmission of various psychiatric disorders

Table 6–2. Relative risks for psychiatric disorders
Figure 6–1. Genetic linkage and recombination.
Figure 6–2. Schematic representation of a microsatellite marker.
Table 6–3. Candidate genes for schizophrenia
Table 6–4. National Institute of Mental Health Collaborative Study of Affective Disorders:
rates of illness in interviewed first-degree relatives
Table 6–5. Candidate genes for mood (affective) disorders
Summary Key Points

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 4
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
 New research
methodologies and
techniques hold the
promise of determining
the location, nature, and
product of the genetic
contribution to many
illnesses. Table 6–1
presents a summary of
the research evidence in
support of genetic
transmission for various
psychiatric disorders.

TABLE 6–1. Evidence

in support of genetic
transmission of
various psychiatric
disorders

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 5
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
As seen in Table 6–2, 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.

TABLE 6–2. Relative risks for psychiatric disorders

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 6
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
Genetic linkage analysis is a technique based on exceptions to Mendel’s 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 6–1).

FIGURE 6–1. Genetic linkage and

recombination.

Depicted is a hypothetical family (circles: females;

squares: males) transmitting an autosomal dominant
disease. The disease locus A (containing either the
defective allele a1 or its normal counterpart a 2) lies
close to a marker locus B (containing marker alleles b 1
and b2). The mother is affected with the disease
(shaded symbol) and is heterozygous at both the
disease and the marker loci. The father is unaffected
(open symbol) and is homozygous at both loci.
Because the disease and marker loci are genetically
linked (i.e., they lie near each other), crossing over
rarely occurs between them. Most children who inherit
the disease allele a 1 also receive the b1 marker allele
from their mother. Occasionally, a recombination event
(i.e., “crossing over”) occurs in the mother, and she
transfers a chromosome bearing the b 2 marker allele
along with the disease allele (as occurred in the
daughter labeled “recombinant”). The frequency of
such recombinants increases as the distance between
the disease and marker locus increases.

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 7
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
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 6–2, 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.

FIGURE 6–2. Schematic representation of a microsatellite marker.

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 the
variable repeating DNA sequence termed a microsatellite marker. For a dinucleotide repeat, each box
represents 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 two
repeats. (This is a simplification; most commonly there are 15–20 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 the polymerase chain reaction (PCR) and is shown for only one of the
two chromosomes of the father. Because the length of the fragment amplified is bounded by the primers, which
are attached to nonrepeating sequences outside the microsatellite region, the length of the product of this
reaction 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. The presence of the bands is determined by autoradiography. Individuals have two bands that
correspond to the lengths of the amplified fragments. Each band is a marker for this region of the long arm of
its own chromosome. The inheritance of these fragments can then be followed through all members of a
pedigree whose DNA is available for the PCR reaction. Genotypes for each of the members of the hypothetical
pedigree are 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 the
microsatellite marker is located close to the disease gene.
(continued)

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 8
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
 FIGURE 6–2. (continued)

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 9
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
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 6–
3).
TABLE 6–3. Candidate genes for schizophrenia

(continued)

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 10
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
TABLE 6–3. (continued)

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 11
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
The results of a very large NIMH collaborative study (2,226 interviewed relatives) that used the RDC
for interviewed relatives are summarized in Table 6–4. 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 quite
different from those for schizoaffective disorder of bipolar type, provided evidence that certain types
of schizoaffective disorder may not be related to bipolar disorder.

TABLE 6–4. National Institute of Mental Health Collaborative Study of Affective Disorders:
rates of illness in interviewed first-degree relatives

Source. Data from Andreasen et al. 1987.

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 12
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
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 6–5.
TABLE 6–5. Candidate genes for mood (affective) disorders

(continued)
The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 13
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
TABLE 6–5. (continued)

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 14
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
 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 role
in 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 NMDAR are promising candidate genes for bipolar
illness.
 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).

(continued)

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 15
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
 CHAPTER 6 • Key Points (continued)

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

and protein and RNA functions can be a powerful strategy for discovering
psychiatric 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.

The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 16
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org