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Chapter 6. Genetics

Prabhakara V. Choudary, Ph.D., F.R.S.C.; James A. Knowles, M.D., Ph.D.
DOI: 10.1176/appi.books.9781585623402.303582

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Excerpt

Most important discoveries are usually not solved in one "Eureka" moment, as movie scripts sometimes suggest, . . . but require scientists to make not one, but a number of original discoveries and to persist in pursuing them until a discovery is complete.

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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 a2) lies close to a marker locus B (containing marker alleles b1 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 a1 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 b2 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.

FIGURE 6–2. Schematic representation of a microsatellite marker. Note. 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.
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TABLE 6–1. Evidence in support of genetic transmission of various psychiatric disorders
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TABLE 6–2. Relative risks for psychiatric disorders
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TABLE 6–3. Candidate genes for schizophrenia
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TABLE 6–4. National Institute of Mental Health Collaborative Study of Affective Disorders: rates of illness in interviewed first-degree relatives
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TABLE 6–5. Candidate genes for mood (affective) disorders
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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).

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.

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Sample questions:
1.
Underlying the optimism for impending breakthroughs in psychiatric genetics are the remarkable advances taking place in the field of human molecular genetics. Which of the following statements concerning human genetics is false?
2.
There is considerable evidence in support of genetic transmission of various psychiatric disorders. For which of the following psychiatric disorders is genetic transmission supported by family risk studies, twin studies, adoption studies, and molecular studies?
3.
Adoption studies are based on the knowledge that adoption separates the two major influences parents have on their children, namely, genes and rearing. Several types of adoption studies have used which of the following as an accurate description of the "cross-fostering strategy"?
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