The growing number of reports on candidate genes an genomic regions of interest in bipolar disorder reveals a tremendously active field of study. As with other complex psychiatric syndromes, these early findings will require a great deal of effort to replicate and clarify. This review serves both as an update and an introduction to some of the issues confronting investigators. Potential strategies in study design, population selection, and molecular methods are explored as well.

Molecular genetic studies of complex disorders require a number of parallel strategies. Many of the more familial psychiatric syndromes are highly prevalent and may represent a collection of a number of distinct genetic subtypes and possibly a number of nongenetic subtypes. A nongenetic form of illness may appear clinically indistinguishable from a genetic form. These nongenetic subtypes of a syndrome would be considered phenocopies. In this and the subsequent issue of CNS Spectrums, a number of papers are presented that review the current state of psychiatric genetics of major disorders. Clinical strategies to narrow phenotypes and better define study populations are paired with laboratory and statistical strategies to optimize both candidate gene and genome scanning methods.

In this issue, Kennedy and colleagues focus on a review of the genetics of schizophrenia, highlighting genome scans already completed and studies on special populations. Schindler and colleagues present a unique and efficient method for defining the homogeneity of a study population, surname analysis, and the importance of population selection in the design of genetic studies. Macedo and colleagues demonstrate the study of anticipation in bipolar mood disorder. Genetic anticipation is the observation of an earlier age of onset and greater disease severity in younger generations. This pattern has been associated with dynamic repeat expansions in the DNA in several neuropsychiatric disorders, and represents a good example of a unique genetic mechanism causing a unique phenotypic pattern. Nicolini and colleagues present work done to date on obsessive-compulsive disorder.

The genetics of schizophrenia are characterized by a set of complex questions, with few answers forthcoming. However, molecular genetic approaches remain the most promising avenue to the understanding of etiologic mechanisms. Powerful discoveries may arise in the near future from candidate gene studies that are benefiting from the extensive neurobiology research in schizophrenia over the past decades. Furthermore, there are promising new divisions of the phenotype into more manageable subtypes that may make both candidate gene and genome scan studies more revealing. The following review discusses selected highlights of the epidemiology, molecular genetic strategies, candidate genes, and genome scan investigations in schizophrenia.

Substance use disorder (SUD) pedigrees identified through an attention deficit/hyperactivity disorder (ADHD) proband may be helpful in teasing apart the genetic risks for both ADHD and SUD (ie, alcohol or drug use). Pedigrees segregating for both SUD and ADHD may represent a subset of both of these common disorders that share a related genetic basis. We determined the number of SUD and ADHD pedigrees in a sample of 175 ADHD probands. We found 52 ADHD pedigrees, indicating that at least 29.7% were familial cases. We also found 50 SUD pedigrees; 13 families contained both an alcohol and a drug pedigree, 35 families were alcohol-only pedigrees, and two families were drug-only pedigrees. The incidence of drug-only pedigrees is significantly higher (P<0.01) in families with familial ADHD. This was also true for families with both drug and alcohol pedigrees (P<0.01). The total number of SUD pedigrees and the families with alcohol-alone pedigrees were not significantly different in ADHD pedigrees compared with nonfamilial ADHD families.

Genetic anticipation refers to an inheritance pattern within a pedigree showing a decrease in age of onset or an increase in disease severity or both in successive generations. This phenomenon has become the focus of important research in schizophrenia and bipolar mood disorder. The results to date have been controversial and far from conclusive. To attempt to resolve some of the earlier findings, we compared age at onset and disease severity between two generations in 24 Portuguese families ascertained for genetic linkage studies of bipolar mood disorder. There was a significant decrease in age of onset (P<. 00001) and increase in frequency of episodes (P<.0001)from the first to the second generation. This difference was significant under each of the four data-sampling schemes, one of which excluded probands. The second generation experienced onset 12.4 to 15.9 years earlier and illness 2.3 to 2.6 times more severe than did the first generation. We found no evidence for a specific effect in anticipation related to the transmitting parent's sex. Results of the present study, analyzed carefully for a variety of possible biases, suggest evidence for genetic anticipation in these Portuguese bipolar families.

The “Genetics of Obsessive-Compulsive Disorder” session at the Third International Obsessive-Compulsive Disorder Conference focused on the strong evidence of familial transmission of obsessive-compulsive disorder (OCD) and the new strategies available for molecular genetic research in this area. The opportunity to create a truly collaborative approach to the genetic study of OCD with standard methodology and large-scale cooperation among groups was emphasized. The importance of phenotype definition, including systematic subtyping, was discussed in the context of reducing heterogeneity and false-positive results.

Many psychiatric disorders are influenced by genetic factors, but the genetic components of complex diseases may not follow clear inheritance patterns. Although the patients may share a common clinical phenotype, the cause of the syndrome may consist of a heterogeneous collection of both genetic and/or environmental components. One method to minimize genetic heterogeneity in studies of complex disorders is to select a very homogenous study population. The average number of families with the same last name, when corrected for population size, is an excellent marker for the degree of homogeneity. We used surname analysis to evaluate the homogeneity of the Portuguese population of Madeira, comparing it with previous data on the homogeneity of populations of mainland Portugal, the Azores, and both rural and urban US populations. The average number of families with the same last name corrected for population size was 33.84 in Madeira, 30.88 in the Azores, and 21.42 in Coimbra (mainland Portugal) compared with 1.13 in rural and 0.38 in urban United States. This surname analysis supports the premise that the Portuguese population is a highly homogenous population, with the highest homogeneity in Madeira and the Azores, making it a good study population for molecular genetic analyses.

Attention-deficit/hyperactivity disorder (ADHD) has an early childhood onset in the majority of cases. This has a considerable impact on the development of the affected individual, both directly (as a result of the symptoms) and indirectly (through the stresses imposed upon school, learning, socialization, and family life). Several lines of evidence point to a genetic component to ADHD. Family studies show a familial aggregation of ADHD, with a five- to sixfold increase in the incidence of ADHD among first-degree relatives. Twin studies reveal a higher concordance rate for ADHD among monozygotic twins compared with dizygotic twins. To date, molecular genetic research has focused on candidate genes in the dopaminergic system. Genes studied include the D2A1 allele of the dopamine D2 receptor gene, the dopamine transporter gene, and the dopamine D4 receptor gene. One of the major limitations to the study of the genetics of behavioral disorders in children has been the overlap among syndromes, including oppositional defiant disorder, conduct disorder, persistent (adult) ADHD, and bipolar disorder. Future research must address weaknesses in existing studies, including small samples sizes, restricted statistical power, and confounding factors such as comorbid illnesses, clinical heterogeneity with variable symptom severity, and unclear phenotypic boundaries.

Neuropsychiatry, like many other biomedical sciences, has been revolutionized by the advances in genomic technologies over the years. The advent of PCR (polymerase chain reaction) and the sequencing of the human genome have provided invaluable insights into the molecular genetics of the various psychiatric disorders through the study of candidate genes and linkage analyses. However, biological phenotype is dictated by protein expression, which has been shown to stray from the genetic blueprint designated by the genome. Consequently, the field of proteomics has recently emerged as a powerful means of exploring protein structure, function, and expression patterns. The ability to study disease at the gene and protein levels presents a tremendous opportunity for neuropsychiatric research, particularly in terms of the potential for developing therapeutic agents for novel protein targets.