Kaplan + Sadock's Synopsis of Psychiatry, 11e

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Chapter 1: Neural Sciences

different families or populations), or polygenic inheritance (risk for disease increases only if susceptibility variants at multiple genes act in concert). Mapping a complex disorder involves sev- eral component steps, including definition of the phenotype to be studied, epidemiological studies to determine the evidence for genetic transmission of that phenotype, choice of an infor- mative study population, and determination of the appropriate experimental and statistical approaches. Genetic Epidemiological Approaches Genetic epidemiological investigations provide quantitative evi- dence regarding the degree to which a given trait aggregates in families and, furthermore, can suggest to what degree such aggregation reflects a genetic contribution to the etiology of the trait. Family studies compare the aggregation of disease among the relatives of affected individuals compared to control sam- ples. Because these studies do not differentiate between genetic and environmental contributions to such familial aggregation, they provide only indirect evidence regarding the heritabil- ity of a trait. Often these studies measure the relative risk ( l ),

within a species; in humans it is hoped that discoveries about the relationship between genotypes and phenotypes will revo- lutionize our understanding of why and how some individuals but not others develop common diseases. This hope is particu- larly strong for psychiatry, as our knowledge of the pathogenic mechanisms of psychiatric disease remains sparse. Genetic mapping studies aim to identify the genes impli- cated in heritable diseases, based on their chromosomal loca- tion. These studies are carried out by investigating affected individuals and their families through two approaches, linkage and association (Fig. 1.7-1). It is now straightforward to geneti- cally map Mendelian traits (traits for which a specific genotype at one particular locus is both necessary and sufficient to cause the trait). Psychiatric diseases, however, do not follow simple Mendelian inheritance patterns but rather are examples of eti- ologically complex traits. Etiological complexity may be due to many factors, including incomplete penetrance (expression of the phenotype in only some of the individuals carrying the disease-related genotype), the presence of phenocopies (forms of the disease that are not caused by genetic factors), locus het- erogeneity (different genes associated with the same disease in

Gene Mapping Strategies

Linkage Analysis

Genome Wide Association

Pedigree Analysis

Case-Control

Family-Trios

Affected Sib Pair Analysis

Affected individuals and matched unaffected controls sampled from population Tests for statistical association of alleles and disease in cases versus controls. 1) Can detect common variants of small effect. 2) Does not require collection of family data.

Multigenerational families with multiple affected individuals Identify genetic markers that cosegregate with disease phenotype 1) Can detect rare variants of large effect. 2) Gains power by incorporating information about familial relationships into the model.

Affected individual and parents

Study Subjects

Two or more affected siblings

Identify chromosomal regions shared by siblings concordant for disease.

Tests for association using non-transmitted parental chromosome as control.

Basic Idea

1) Can detect common variants of small effect. 2) Robust to problems of population stratification.

1) Robust to differences in genetic composition of study population. 2) Easier to collect clinical samples compared to special pedigrees. 3) Allows incorporation of enviromental data.

Strengths

1) About two-thirds as powerful as case-control designs. 2) Difficult to collect samples for late onset diseases.

1) Increased false positive rate in the presence of population stratification. 2) Requires large sample sizes.

1) Limited power to identify common variants of small effect. 2) Cost intensive.

1) Limited power to identify common variants of small effect.

Limitations

Figure 1.7-1 Comparison of gene-mapping strategies. Genetic mapping approaches can be divided into those that rely on linkage analysis and those that rely on association analysis. Linkage studies can be further categorized as either focused on investigation of pedigrees or focused on investigation of sib pairs. Association studies can be categorized as either case–control or family-based. Some of the key features as well as advantages and disadvantages of these different approaches are shown. (From Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry . 9 th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:321.)