Genes for normal and diseased mental states

The availability of highly polymorphic DNA markers spanning the human genome, coupled with results from classical family, twin and adoption analyses, has stimulated the search for mutations that predispose to manic depression, schizophrenia, autism, substance abuse and a host of other psychiatric diseases. A recent meeting (World Congress on Psychiatric Genetics, New Orleans, October 2-5, 1993) drew over 400 attendees, signifying increased interest in psychiatric genetics. One of the triumphs of the 20th century is the characterization of mutations that cause hereditary diseases such as Duchenne muscular dystrophyL2 and cystic fibrosis~5. Identification of mutations that predispose to inherited neurological ailments, including early onset Alzheimer's disease 6 and Huntington's chorea 7, and to mental retardation associated with fragile X syndrome s-10 , has stimulated the search for genes that cause or contribute to complex psychiatric disorders such as manic depression, schizophrenia, autism, alcoholism and drug abuse. To what extent ate behaviour and personality controlled by our genes? The answer will have considerable scientific, social, ethical and philosophical implications. Despite false starts tt,t2, we are now on the road to identifying the genes involved in at least some major mental illnesses. Evidence for a genetic component in psychiatric diseases comes largely from three complementary types of observation13: first, some psychiatric ailments aggregate in families; second, in those familial diseases, concordance is usually higher for monozygotic than for dizygotic twins; and third, biological relatives of adopted individuals with familial psychiatric illnesses often have an increased risk of disease compared with the patients' adoptive relatives. However, genetic analysis of psychiatric illnesses is complex. Such diseases often show incomplete penetrance and may have phenocopies that result from environmental, rather than genetic, factors; diagnosis of such disorders is often anabiguous. Some psychiatric diseases may be caused by the combined effect of multiple genes (as well as environmental factors), such that the influence of a single gene might be small. The usefulness of family, twin and adoption studies in detecting such predisposing genetic factors has been improved by standardized diagnostic guidelines (see, for example, Ref. 14), by better mathematical models and computer programs for analysing data, and by careful choice of affected and control groups. Work presented at this meeting (see Ref. 15 for abstracts) confirmed and extended previous evidence that certain psychiatric diseases have a genetic component. Relationships between different disorders were also discussed; for example, Tourette's syndrome (TS), in which affected individuals suffer uncontrollable tics and involuntarily utter obscenities, is associated with a wide spectrum of behavioural problems, including panic attacks, mood disturbances, sexual disorders and abuse of alcohol and drugs. These associated traits appear to be under the pleiott~opic control of the gene(s) that predispose to 'IS, since they are all much more prevalent in relatives who are also TS sufferers than in non-affected relatives (D.E. Comings, Duarte, California). Extensive family, social and psychiatric records of relatively isolated populations can be a powerful resource in genetic studies of psychatric illnesses. For example, registries extending over several centuries in a rural area of Norway have been used (J.E. Andersen et al., Oslo, Norway) to identify three founder males who lived in the 17th and 18th centuries and whose behaviour was insane, deviant or suicidal; the present-day descendants of these founders were traced. Of 120 patients who had attended the local psychiatric clinic in recent years, 60°6 were related to one or more founder. Descendants of founders who had psychotic and suicidal behaviour also tended to have these problems. In addition, individuals' use of mental health services increased with their relatedness to the founders. No..,'mal personality traits also have a significant genetic component. C.R. Cloninger (St Louis) described studies using lengthy self-report inventories that define a person's temperament and character. Temperament was divided into four components, and character into three; each component was further subdivided into multiple categories. Twin and adoption studies showed that temperament was 40-60°,6 heritable, but character only 10-33% heritable. Once a genetic contribution to the aetiology of a psychiatric trait has been established, the gene(s) and mutations involved remain to be characterized. Expansion of trinucleotide repeats, for instance, occurs in numerous genetic disease# 6, including fragile X syndrome, Huntington's disease and myotonic dystrophy, and a similar mechanism may underlie some psychiatric disorders rt, Kay Davies (Oxford, UK) reviewed fragile X syndrome, the second major cause of mental retardation after Down's syndrome. This affliction involves both physical and mental abnormalities, and is associated with expansion of a (CGG) n trinucleotide repeat near the 5' end of a gene called FMR-1, on the X chromosome (Xq27). The risk of having an affected child can be predicted from the number of repeats in carriers, and the severity of mental retardation increases with the number of repeats. Fragile X syndrome shows anticipation, a phenomenon in which the severity of a disease increases from one generation to the next, because of expansion of trinucleotide repeats. Unaffected individuals have 0-50 copies; carriers, 50-150; and affected individuals, many hundreds, even thousands. However, the genetics of fragile X is more complicated flhan was at first thought. For example, a point mutation or a deletion in the FMR-I