Mohammed T. Abou-Saleh

Principles and Practice of Geriatric Psychiatry.Editors: Professor John R. M. Copeland, Dr Mohammed T. Abou-Saleh and Professor Dan G. BlazerCopyright & 2002 John Wiley & Sons LtdPrint ISBN 0-471-98197-4 Online ISBN 0-470-84641-069Genetics of Affective DisordersJohn L. Beyer and David C. SteffensDuke University Medical Center, Durham, NC, USAThe observation that affective disorders aggregated in families hasbeen present from the time of Socrates, through the analysis ofSigmund Freud, the behavioral work of B. F. Skinner and in thegenetic studies of the past 40 years. In each of these views, thefamily unit recurs as a major focal point in mood disorders. Buthow is one to understand this relationship? Affective disordersmay be aggregated in families for a variety of reasons, such asshared genes, shared culture, shared adversity, or multiple otherreasons.In the past, research in families followed two non-overlappingtracks: genes and environment. This was knownpopularly as ‘‘nature vs. nurture.’’ In recent years, researchershave become more aware that attempts to dichotimize the causeof affective disorders into ‘‘genes’’ and ‘‘environment’’ hashindered understanding of mood disorders. The emergingscience of genetic epidemiology focuses on causes, distributionand control of disease in groups of relatives, and with inheritedcauses of disease in populations 1 . Thus, the goal of geneticresearch is to identify both genetic and environmental causes ofillness. In fact, certain types of genetic studies (e.g. twin studies)have provided some of the strongest evidence that environmentplays a significant etiologic role in the expression of mentalillness.Research findings clearly show that the etiology of mooddisorders in early and middle adulthood is multifactorial. Bothenvironmental factors (e.g. parental loss, stroke) and geneticfactors are strongly implicated, although what occurs and howthis happens remain as areas of intense research. In recent years,investigations in late-life affective disorders have asked the samequestions regarding cause, but the answers suggest that there areetiologic differences among affective disorders at different ages.This observation only leads to new questions. Is the developmentof late-life affective disorders related to the genetic make-up of theindividual? Are late-life affective disorders a continuation ofmood disorders which developed earlier in life or do theyrepresent unique reactions to specific challenges presented bythe process of aging? If so, what are these challenges and how arethey related to an individual’s genetic make-up? How do geneticand environment factors contribute to the understanding ofdiagnostic subsets of affective disorders?In this chapter, we will review the current state of geneticresearch of affective disorders, primarily studied in early andmiddle life. Then we will contrast that with what is known aboutaffective disorders that have their first onset in late life. Finally, wewill discuss the implications of these findings and suggest atheoretic framework to understand genetic and environmentalcontributions to geriatric affective disorders.GENETIC INFLUENCES IN AFFECTIVE ILLNESSThere are four types of studies that demonstrate the influence ofgenetic factors on the development of disease: (a) studies offamilial aggregation; (b) twin studies; (c) adoption studies; and (d)association and linkage studies of an illness with a genetic marker.Family StudiesFamily studies are the most basic research form in evaluatinggenetic risk. They attempt to answer the question, ‘‘Does thisdisorder run in families?’’ Logically, if genes cause a disorder, thenrelatives of an individual affected by that disorder (the proband)should be more likely to have that particular disorder than othersin the general population, since they share common genes.However, common environmental factors may also contributeto the clustering in families. Therefore, the major goal of familystudies is to understand the magnitude and patterns of a disease’saggregation, rather than identify specific genetic causes.In affective disorders, six landmark studies 2–7 have supportedthe observation of familial aggregation. First-degree relatives(parents, siblings, offspring) of depressed patients are twice aslikely to develop depression than those in the general population.First-degree relatives of bipolar patients are at even greater riskfor developing bipolar disorder (incidence of 3.7–17.5%, dependingon the study). The risk of bipolar disorder is less in seconddegreerelatives (grandparents, grandchildren, aunts, uncles) ofbipolar patients, although still elevated over the general population.Twin StudiesTwin and adoption studies are especially helpful in answering thenext question, ‘‘What are the relative contributions of genes andenvironment to the development of a mental disorder?’’ Twinsprovide a natural experiment in genetics. Monozygotic (MZ)twins, known as identical twins, share 100% of their genes.Dizygotic (DZ) twins, known as fraternal twins, share approximately50% of their genes, the same proportion as with othersiblings. In the ‘‘twin experiment’’, it is assumed that bothdizygotic and monozygotic twins share the same environment, butonly monozygotic twins share the same genes. Thus, if genes are aputative cause for a disorder, then the MZ co-twin of a probandshould be at higher risk to develop a disorder than the DZ co-twinof a proband. This is expressed as the concordance rate.Principles and Practice of Geriatric Psychiatry, 2nd edn. Edited by J. R. M. Copeland, M. T. Abou-Saleh and D. G. Blazer&2002 John Wiley & Sons, Ltd