Elsevier

Biological Psychiatry

Volume 45, Issue 5, 1 March 1999, Pages 522-532
Biological Psychiatry

Complex Genetics and Implications for Psychiatry
Basic concepts in the study of diseases with complex genetics

https://doi.org/10.1016/S0006-3223(98)00316-3Get rights and content

Abstract

Most diseases run in families—this is also true of virtually all psychiatric disorders. Twin and adoption studies have shown that most psychiatric disorders have a genetic component, yet very few genetic factors are known, as is true for most disorders with a complex genetic origin. Here I review, for nongeneticists, some of the basic terminology and concepts used when studying complex genetic diseases, with examples from psychiatric genetics. This review is intended to help in the understanding and critical evaluation of reports on genetics of psychiatric illnesses in the literature.

Section snippets

How do we know that predisposition to a disease is genetic?

Most diseases run in families—but that is not enough to conclude that genetic factors are involved, since infectious diseases or nongenetic traits such as malnutrition or attendance of medical school also run in families. Twin and adoption studies discriminate between familiality due to genetic or due to environmental influences (geneticists mean with the latter any nongenetic factor, including chance and measurement error). Adoption studies have shown that the risk of an adoptee of having a

Alleles—the variations in the genome

In general, an allele is one of several forms of any defined DNA sequence in the genome, whether it is a gene or an anonymous DNA sequence. Such a defined place in the genome is called a locus [plural loci, please see also the glossary (Appendix 1) for a summary of terms explained in this section]. If a disease is inherited in a simple manner, the inheritance of disease alleles can be followed in pedigrees.

Although any base pair change is caused molecularly by mutation, the word mutation is now

Diseases can have a complex genetics for many reasons

A Mendelian disease runs in families in a strict dominant, recessive, or X-linked fashion. Hundreds of such disease loci have been mapped, and over 600 genes involved in genetic diseases have already been identified (Gelehrter et al 1998); however, so far there are only very few examples of psychiatric illnesses inherited in a strictly Mendelian fashion (see Brunner et al 1993 for such an example). Since there is some variation in onset and clinical course even in strictly Mendelian disorders

Mapping and cloning of mendelian disease genes: parametric linkage analysis

Before going into the problems of complex disorders, let us review how Mendelian disease genes were mapped so successfully in the past 10 years (Collins 1995). To identify such genes, families are ascertained, preferentially large pedigrees, DNA is isolated from blood, and linkage analysis is performed in which SSLPs from all over the genome are tested—i.e., PCR reactions are performed on DNA from each member of the pedigree with 200–500 SSLP markers. The logic of linkage analysis is

Heterogeneity

One complication in linkage mapping is if a disease runs in a Mendelian fashion in families, but in each family a different gene, usually on a different chromosome, causes the disease. This is called heterogeneity. One prime example is deafness, for which so far over 30 different loci have been identified (Petit 1996). Deafness can be inherited in a recessive, dominant, or X-linked fashion, and each runs in families in a fairly Mendelian fashion, so that it seems often (but not always) to be a

Nonparametric linkage analysis

To avoid some of the problems of selecting a very specific model, while still using some of the power of linkage analysis, nonparametric, i.e., mode-of-inheritance-independent, methods of linkage analysis were developed, called affected sib pair (ASP) methods or the more general affected pedigree member method (APM) (Weeks and Lange 1988). In these methods, only sibpairs or other pairs of affected relatives are studied, which means the power of seeing alleles segregating in large pedigrees is

Case–control association studies

Linkage-based studies are based on following marker alleles that are close to a mutation on a specific chromosomal segment. These approaches do not make any biological assumptions about the disease, in fact they are performed in exactly the same fashion for diabetes, hypertension, or alcoholism. Once a location is found, the nature of the linked marker is irrelevant, all it does is “mark” the region of the chromosome. Popular press releases often confuse identification of linkage with finding a

Family-based association studies

A better way to overcome the population-stratification problem in case–control studies, however, are newer, family-based approaches, called haplotype relative risk (HRR) and transmission disequilibrium test (TDT) (see Figure 2B–D). The idea in these studies is to use the nontransmitted allele from the parents of an affected proband as internal controls (Figure 2B). In this manner, the same individuals, parents of affected subjects, provide both the test and the control sample, and thus the

Which method might work for which disease?

How can we decide between the methods mentioned above for our particular interest (see Table 1 for a simplified summary) ? When the disease is inherited in a clearly Mendelian fashion, there is no question that parametric linkage analysis is by far the most powerful method to locate a gene. Several pedigrees have been identified in which bipolar disorder segregates in an apparently Mendelian dominant fashion, and other pedigrees in which it seems X-linked; however, since a disease such as

Genome-wide association studies

In any form of linkage study, with a few hundred markers we can search blindly, without biological hypotheses, over the whole genome. In contrast, in TDT, specific alleles of a candidate gene are tested for association with the disease, and even different alleles within the same gene may be independent. Although the candidate gene approach seems appealing when we have a good hypothesis about the disease, genetic studies often identified genes that were never thought of as candidate genes: a

Summary

In summary, at the present time, there is no recipe for how to proceed to identify genes involved in complex diseases such as psychiatric illnesses. Currently, mixed approaches using linkage, association, and linkage disequilibrium are most often performed; for example, once a few chromosomal regions have been tentatively found to be linked, linkage disequilibrium is tested if suitable, and used to narrow down the region, and candidate genes in the most promising regions are scrutinized for

Acknowledgements

Research on Mental Illness in my laboratory is funded by the National Association for Research on Schizophrenia and Affective Disorders (NARSAD), the Nancy Pritzker Network on Depression Research, and the NIAAA.

I thank Adele Barres for help with figures, Huda Akil for many useful discussions, and Michael Boehnke, Scott Stoltenberg, Stanley Watson, James Meador-Woodruff, and Elizabeth Young for critical reading.

This work was presented in December 1997, at the American College of

References (47)

  • C.L. Barr et al.

    Population frequencies of the A1 allele at the dopamine D2 receptor locus

    Biol Psychiatry

    (1993)
  • R. Freedman et al.

    Alternative phenotypes for the complex genetics of schizophrenia

    Biol Psychiatry

    (1999)
  • A.K. Malhotra et al.

    Benefits and pitfalls encountered in psychiatric genetic association studies

    Biol Psychiatry

    (1999)
  • K. Blum et al.

    Allelic association of human dopamine D2 receptor gene in alcoholism

    JAMA

    (1990)
  • D.L. Brown et al.

    Efficient strategies for genomic searching using the affected-pedigree-member method of linkage analysis

    Am J Hum Genet

    (1994)
  • H.G. Brunner et al.

    Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A

    Science

    (1993)
  • A. Chakravarti

    It’s raining SNPs, hallelujah?

    Nat Genet

    (1998)
  • Collins FS (1995): Positional Cloning moves from perditional to traditional. Nat Genet 9:347–350. Collins FS, Guyer MS,...
  • C. Dib et al.

    A comprehensive genetic map of the human genome based on 5,264 microsatellites

    Nature

    (1996)
  • Falk CT, Rubinstein P (1987): Haplotype relative risks: An easy reliable way to construct a proper control sample for...
  • N.B. Freimer et al.

    Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22–q23

    Nat Genet

    (1996)
  • T.B. Friedman et al.

    A gene for congenital, recessive deafness DFNB3 maps to the pericentric region of chromosome 17

    Nat Genet

    (1995)
  • J. Gelernter et al.

    The A1 allele at the D2 dopamine receptor gene and alcoholism. A reappraisal

    JAMA

    (1993)
  • T.D. Gelehrter et al.
  • E.S. Gershon et al.

    Closing in on genes for manic-depressive illness and schizophrenia

    Neuropsychopharmacology

    (1998)
  • E.I. Ginns et al.

    A genome-wide search for chromosomal loci linked to bipolar affective disorder in the Old Order Amish

    Nat Genet

    (1996)
  • J. Hebebrand

    A critical appraisal of X-linked bipolar illness. Evidence for the assumed mode of inheritance is lacking

    Br J Psychiatry

    (1992)
  • R.H. Houwen et al.

    Genome screening by searching for shared segmentsMapping a gene for benign recurrent intrahepatic cholestasis

    Nat Genet

    (1994)
  • K.S. Kendler et al.

    The genetics of schizophreniaA current, genetic-epidemiologic perspective

    Schizophr Bull

    (1993)
  • W.C. Knowler et al.

    Gm3;5,13,14 and type 2 diabetes mellitusAn association in American Indians with genetic admixture

    Am J Hum Genet

    (1988)
  • H.M. Lachman et al.

    Human catechol-O-methyltransferase pharmacogeneticsDescription of a functional polymorphism and its potential application to neuropsychiatric disorders

    Pharmacogenetics

    (1996)
  • E. Lander et al.

    Genetic dissection of complex traitsGuidelines for interpreting and reporting linkage results

    Nat Genet

    (1995)
  • E.S. Lander et al.

    Genetic dissection of complex traits

    Science

    (1994)
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