Behaviour and genes

Behaviour runs in families

We tend to resemble our parents, siblings, and other close relatives not just in the way we look but in the way we behave. However, the types, patterns, and causes of familial behavioural traits are extremely varied. They range from rare single gene disorders, such as Huntington's disease, that present with dramatic changes in behaviour in adult life, to commoner but more genetically complex disorders, such as schizophrenia and manic depression, through to normal variation in traits that are usually measured quantitatively, such as personality or intelligence.1 They can also include characteristics such as political or religious persuasion and career choice.

One of the basic pitfalls in studying the genetics of behaviour (or indeed any other type of trait) is to assume that familiality necessarily implies genetic transmission or that strong evidence of familial clustering implies single gene effects. Geneticists have long been aware that mendelian inheritance can be simulated by other mechanisms.2 To illustrate this, McGuffin and Huckle studied the educational histories of the families of a cohort of medical students: they found that attending medical school was roughly 80 times more common in the students' first degree relatives than in the general population and that when complex segregation analysis (a computerised method of exploring the mode of transmission) was performed the “trait” closely resembled an autosomal recessive one.3

A more satisfactory basic model for complex traits is that the phenotype results from a combination of the genotype and the environment to which it is exposed. Environment canbe split into two broad types—shared environment, which acts on all family membersto make them similar, and non-shared experiences that are specific to individuals, whichwould be expected to cause differences in how family members behave.

Experiments of nature

Two types of “natural experiment” enable us to estimate the extent to which complex traits are familial because of shared genes, shared environment, or a combination of both. The first is afforded by twinning and the second by adoption.

Twin studies

The basis of twin studies is that monozygotic or identical twins are naturally occurring clones, having all of their genes in common. On the other hand, dizygotic or fraternaltwins share on average half of their genes. If we assume that the environment shared by twins is roughly the same for monozygotic and dizygotic pairs, then any greater observed similarities in monozygotic than dizygotic pairs should reflect the action of genes. This “equal environments assumption” is open to criticism since there is some evidence that monozygotic pairs report greater environmental similarities (such as dressing the same and sharing friends) than do dizygotic pairs, especially during childhood.4 Nevertheless, the assumption can be tested by incorporating environmental measures in twin studies or by looking at the effects of mistaken zygosity (the twins and their parents believe that they are monozygotic when they are actually dizygotic or vice versa). Sometimes it is also possible to compare the resemblance of monozygotic twins reared together with those reared apart. In practice, these checks suggest that the equal environments assumption is generally valid.5

Figure 1 summarises results from twin studies on various disorders and traits including psychological “symptoms” in normal twins. There are clear differences between monozygotic and dizygotic twins for some phenotypes—schizophrenia,6 manic depressive disorder,7 unipolar depression,4 childhood autism,8 attention deficit hyperactivity disorder,1 and cognitive ability as measured by IQ test1—suggesting genetic effects. For bulimic behaviour 10 and disabling fatigue in childhood,11 there is evidence of familiality (there are positive correlations) but less clear genetic effects (modest differences in the monozygotic and dizygotic correlations).

Fig 1.

Similarity between monozygotic and dizygotic twins in expression of various disorders

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Quantifying nature and nurture

Major advances in quantitative psychiatric genetics have occurred in the past two decades with the increased availability of high speed computing. This has enabled researchers to go beyond merely estimating heritability— that is, the proportion of total phenotypic variance explained by additive genetic affects. It is now possible to accurately quantify both genetic and environmental effects and assess the extent to which a reduced model (such as one with no additive genetic or no common environmental effects) explains the data compared with a full model. A recent application to schizophrenia showed that the heritability may be as high as 80%, and, although this leaves 20% of variance to be explained by the environment, this seems to be entirely of the non-shared type.6 The table shows examples of behavioural disorders or traits that are thought to have a genetic component.

It is also possible to carry out multivariate model fitting that examines two or more disorders or traits at a time.14 For example, life events are generally thought to have a causal relation with depression, but a recent study suggested that at least part of the co-occurrence of life events and depressive symptoms results from genetic and shared environmental influences on the extent to which both are reported.15 A similar approach can be applied to psychiatric syndromes that often occur together. It had been shown that the same genes influence both anxiety and depressive disorder but that the environmental influences on the two types of disorder are apparently distinct.16

Such findings are not an end in themselves. Demonstrating that a disorder is substantially heritable or that a pair of disorders overlap genetically but have different environmental influences leads to two other types of study. The first is to identify the specific environmental factors that co-act or interact with genes and the second is to locate and identify the genes themselves. Here we consider only the latter.

Finding genes

Mapping and positional cloning

Figure 2 shows the general process of positional cloning. A chromosomal region containing a gene that confers susceptibility to the disorder of interest is identified by linkage mapping. The region is then narrowed down by means of various methods until the gene itself is identified. Subsequently, the mutations (or variations) that confer susceptibility to disease are identified. The distribution, level of expression and functions of the gene products can then be studied. The process of positional cloning carries the possibility of incremental benefits for clinical practice in the forms of predictive testing, refined diagnosis and eventually the development of targeted specific treatments.

Fig 2.

Process of positional cloning to find a gene that confers susceptibility to a disorder

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However, conventional linkage analysis requires several assumptions: that there are major gene effects to be detected, that the sample is genetically homogeneous (that is, allof the affected individuals have the same cause of disorder), and that the mode of transmission of the disorder is known. A study of large, multiply affected pedigrees with early onset of Alzheimer's disease has identified mendelian subforms of the disease: three distinct forms have been mapped, and the mutations identified.17 This has not been the case with other psychiatric disorders such as schizophrenia or manic depression. Here a bewildering and apparently contradictory array of positive linkage study results has been reported,18 19 suggesting that single genes of large effect are rare or non-existent and that these disorders are oligogenic (resulting from the combined effects of several genes) or perhaps polygenic (resulting from many genes).

Predicting the clinical impact of mapping genes

The most immediate benefit of identifying genes contributing to common familial psychiatric diseases will be in our understanding of the basic neurobiology of disease, but this should lead on to the discovery of new and more specific drug treatments. It is as much commercial farsightedness as scientific altruism that has led the major pharmaceutical companies into serious investment in genotyping technology and the development of detailed maps of single nucleotide polymorphisms.24 Safer, more effective treatments will obviously be to the benefit of patients, but it is also possible to envisage DNA testing being used to predict which patients will respond to different types of antipsychotic or antidepressant treatment or who will be susceptible to particular side effects. Preliminary evidence suggests that these approaches will work. For example, response to antipsychotic drugs seems to be influenced by genotype at the gene for serotonin receptor 5-HT_2A.25

What about predicting whether someone will develop a psychiatric disorder and attempting to prevent it? Prediction is already possible for rare dementias of early onset, such as Huntington's disease, or single gene forms of Alzheimer's disease. Understanding the molecular basis of these conditions should lead on to the development of effective treatments and preventive methods, but none exists yet. Somewhat paradoxically, genetic predictive testing is much more difficult for commoner disorders such as depression or schizophrenia, where effective treatments exist but were the genetic basis is complex. Psychiatric genetic counselling is already available in some specialist centres, but at present it is possible only to offer empirical figures for those at high genetic risk. For example, the child of a schizophrenic parent has about 10 times the risk of developing the disorder compared with a member of the general population, where the lifetime risk is 1%. The child's risk increases to 16 times if a sibling is already affected and is over 40 times the population risk when both parents have schizophrenia.26

It is likely that individual risk prediction will become more precise once the molecular genetic basis of schizophrenia is better understood, but it is unlikely that risk prediction will ever be better than about 50% accurate since monozygotic twins are discordant for schizophrenia 50% of the time. In our view, this means that DNA based population screening for complex psychiatric disorders (including Alzheimer's disease of late onset) will never become a reality but that screening for high risk relatives probably will. This could have obvious benefits in advising relatives on avoiding risk factors (such as the recreational use of cannabis in the case of schizophrenia) or, more controversially, in attempting prevention with a low dose antipsychotic agents.

There will also be less immediately tangible benefits to sufferers from psychiatric disorders. It has sometimes been feared that “geneticisation” could contribute to the stigma of mental disorder. So far the experience has been just the opposite. Alzheimer's disease is now widely perceived as a “real” disorder with a rapidly unfolding molecular aetiology. We predict that this is the start of a trend and that identifying the genes involved and understanding causation will do much to improve public perception and acceptance of other psychiatric disorders.