Miron Baron

Combined Analysis from Eleven Linkage Studies of Bipolar Disorder Provides Strong Evidence of Susceptibility Loci on Chromosomes 6q and 8q

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

Genetics of schizophrenia and the new millennium : Progress and pitfalls

Schizophrenia (MIM 181500) is a severe and common psychiatric disorder afflicting 1% of the world population. The disease is characterized by psychotic symptoms and by cognitive, affective, and psychosocial impairment. As a leading cause of psychiatric admissions, schizophrenia accounts for a considerable portion of health-care expenditures and is viewed as a major public health concern. Despite extensive research, our knowledge of the structural or functional pathology of schizophrenia is limited. The only etiological factor with a reasonably firm foundation is inheritance, as evidenced by family, twin, and adoption studies that point to substantial heritability (Gottesman and Shields 1982; Gottesman 1991; Kendler and Diehl 1993). In the premolecular era, attempts to discern the underlying genetic mechanism consisted of (1) segregation analysis, testing the fit of observed familial patterns to specific genetic formulations (e.g., single–major-locus, oligogenic, and multifactorial-polygenic models); (2) searching for genetic susceptibility traits, also known as “biological markers,” that segregate with the disorder in families (e.g., neurotransmitter enzymes, receptor proteins, or metabolites; attentional and electroencephalographic measures; and indices based on brain imaging); and (3) linkage studies that used classical gene markers (e.g., leukocyte antigens, blood groups, or serum proteins). However, in spite of numerous studies, the genetic underpinnings of schizophrenia remain elusive. The disorder, which is confounded by a host of factors (e.g., phenotypic diversity, etiologic heterogeneity, incomplete penetrance, unknown mode of inheritance, uncertainty about the number of loci involved and about their interactions, and the existence of nongenetic cases or phenocopies), was consigned to a complex multifactorial etiology, with no firmly established biological correlates (Baron 1986a and 1986b; Risch 1990b; Kendler and Diehl 1993). A single major locus is unlikely as a common mode of inheritance. Oligogenic or polygenic models are plausible alternatives. The advent of molecular genetics was a turning point in schizophrenia research, enabling the systematic application of both reverse genetics (studying random, anonymous DNA markers spanning the genome) and forward-genetics (testing candidate-gene polymorphisms with presumed functional relevance for the disease) (Martin 1987; Baron and Rainer 1988; Owen and Craddock 1996). In this article I review molecular genetic findings about schizophrenia, with an eye toward methodological issues and future research.

Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia

The low-to-moderate resolution of linkage analysis in complex traits has underscored the need to identify disease phenotypes with presumed genetic homogeneity. Bipolar disorder (BP) accompanied by psychosis (psychotic BP) may be one such phenotype. We previously reported a genome-wide screen in a large bipolar pedigree sample. In this follow-up study, we reclassified the disease phenotype based on the presence or absence of psychotic features and subgrouped pedigrees according to familial load of psychosis. Evidence for significant linkage to psychotic BP (genome-wide P<0.05) was obtained on chromosomes 9q31 (lod=3.55) and 8p21 (lod=3.46). Several other sites were supportive of linkage, including 5q33 (lod=1.78), 6q21 (lod=1.81), 8p12 (lod=2.06), 8q24 (lod=2.01), 13q32 (lod=1.96), 15q26 (lod=1.96), 17p12 (lod=2.42), 18q21 (lod=2.4), and 20q13 (lod=1.98). For most loci, the highest lod scores, including those with genome-wide significance (at 9q31 and 8p21), occurred in the subgroup of families with the largest concentration of psychotic individuals (≥3 in a family). Interestingly, all regions but six—5q33, 6q21, 8p21, 8q24, 13q32 and 18q21—appear to be novel; namely, they did not show notable linkage to BP in other genome scans, which did not employ psychosis for disease classification. Also of interest is possible overlap with schizophrenia, another major psychotic disorder: seven of the regions presumed linked in this study—5q, 6q, 8p, 13q, 15q, 17p, and 18q—are also implicated in schizophrenia, as are 2p13 and 10q26, which showed more modest support for linkage. Our results suggest that BP in conjunction with psychosis is a potentially useful phenotype that may: (1) expedite the detection of susceptibility loci for BP and (2) cast light on the genetic relationship between BP and schizophrenia.

Genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health genetics initiative suggests putative loci for bipolar disorder, psychosis, suicide, and panic disorder

We conducted a 9-cM genome scan in a large bipolar pedigree sample from the National Institute of Mental Health genetics initiative (1060 individuals from 154 multiplex families). We performed parametric and nonparametric analyses using both standard diagnostic models and comorbid conditions thought to identify phenotypic subtypes: psychosis, suicidal behavior, and panic disorder. Our strongest linkage signals (genome-wide significance) were observed on chromosomes 10q25, 10p12, 16q24, 16p13, and 16p12 using standard diagnostic models, and on 6q25 (suicidal behavior), 7q21 (panic disorder) and 16p12 (psychosis) using phenotypic subtypes. Several other regions were suggestive of linkage, including 1p13 (psychosis), 1p21 (psychosis), 1q44, 2q24 (suicidal behavior), 2p25 (psychosis), 4p16 (psychosis, suicidal behavior), 5p15, 6p25 (psychosis), 8p22 (psychosis), 8q24, 10q21, 10q25 (suicidal behavior), 10p11 (psychosis), 13q32 and 19p13 (psychosis). Over half the implicated regions were identified using phenotypic subtypes. Several regions – 1p, 1q, 6q, 8p, 13q and 16p – have been previously reported to be linked to bipolar disorder. Our results suggest that dissection of the disease phenotype can enrich the harvest of linkage signals and expedite the search for susceptibility genes. This is the first large-scale linkage scan of bipolar disorder to analyze simultaneously bipolar disorder, psychosis, suicidal behavior, and panic disorder.

Schizoaffective illness, schizophrenia and affective disorders: morbidity risk and genetic transmission

Data on schizoaffective illness, schizophrenia and affective disorders were gathered on first‐degree relatives of schizoaffective probands and matched controls (bipolars, unipolars and schizophrenics). The familial pattern of affective and schizophrenic subtypes of schizoaffective disorder resembled the familial pattern of affective and schizophrenic probands, respectively. The overall risk for the spectrum of schizoaffective and affective disorders was higher among relatives of schizoaffective‐manic as compared to relatives of schizoaffective‐depressive probands, although the difference fell short of significance. When tested for consistency with multiple threshold hypotheses of genetic transmission, schizoaffective illness did not qualify as either a more extreme form of affective illness nor as a disorder that occupies an intermediate position between bipolar and unipolar disorders or is genetically milder than affective disorder. The implications of diagnostic subtyping for genetic research in the major psychoses were discussed.

Evidence for a putative bipolar disorder locus on 2p13-16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21-24, 13q32, 14q21 and 17q11-12.

Bipolar disorder (BP) is a severe and common psychiatric disorder characterized by extreme mood swings. Family, twin and adoption studies strongly support a genetic component. The mode of inheritance is complex and likely involves multiple, as yet unidentified genes. To identify susceptibility loci, we conducted a genome-wide scan with 343 microsatellite markers in one of the largest, well-characterized pedigree samples assembled to date (373 individuals in 40 pedigrees). To increase power to detect linkage, scan statistics were used to examine the logarithm of odds (lod) scores based on evidence at adjacent chromosomal loci. This analysis yielded significant evidence of linkage (genome-wide P<0.05) for markers on 2p13–16. Standard linkage analysis was also supportive of linkage to 2p13–16 (lod=3.20), and identified several other interesting regions: 4q31 (lod=3.16), 7q34 (lod=2.78), 8q13 (lod=2.06), 9q31 (lod=2.07), 10q24 (lod=2.79), 13q32 (lod=2.2), 14q21 (lod=2.36) and 17q11–12 (lod=2.75). In this systematic, large-scale study, we identified novel putative loci for BP (on 2p13–16, 8q13 and 14q21) and found support for previously proposed loci (on 4q31, 7q34, 9q31, 10q21–24, 13q32 and 17q11–12). Two of the regions implicated in our study, 2p13–14 and 13q32, have also been linked to schizophrenia, suggesting that the two disorders may have susceptibility genes in common.

The Schedule for Schizotypal Personalities (SSP): A diagnostic interview for schizotypal features

The validity and reproducibility of psychiatric diagnosis are crucial to psychiatric research. To establish confidence in assigning schizotypal features, three paradigms estimating the reliability of a new instrument, the Schedule for Schizotypal personalities (SSP), were tested. The first paradigm considered joint, but independent evaluations made by two raters simultaneously. The second paradigm assessed evaluations on different occasions, with a mean interim time of 5.9 months (test-retest procedure). Both reliability paradigms demonstrated high levels of agreement for all of the scaled items. Ninety percent of the intraclass correlation coefficients were 0.80 or better for the joint evaluations, and 70% were 0.80 or better for the test-retest evaluation. The third paradigm measured the reliability of DSM-III Schizotypal Personality Disorder. The kappa value for measuring diagnostic agreement was 0.88. The authors recommend the use of the SSP as an interview schedule and discuss the implications of their findings for genetic and biological research of schizophrenia spectrum disorders.

Genetics of schizophrenia: I. Familial patterns and mode of inheritance

The purpose of this article is to review and condense the available literature on genetic modeling in schizophrenia research. The principles underlying genetic models and the various applications of these models to family data are reviewed. It is concluded that despite the advances in statistical genetics, the mode of inheritance of schizophrenia remains elusive. The conflicting results are attributed to variation in methods for data collection and analysis and to the heterogeneous nature of the disorder. The possibility is also raised that most previous genetic analyses of schizophrenia may have been compromised by methodological drawbacks. Although the use of advanced genetic models in conjunction with adequate data may shed more light on the genetic contribution to schizophrenia, the limitations of this approach in genetically heterogeneous disorders must be recognized. Alternative methods, such as studies with biological susceptibility traits and genetic markers, may be more useful in unraveling the specific genetic components that underlie the transmission of schizophrenia.

Age‐of‐onset and genetic transmission in affective disorders

Age‐of‐onset data were gathered on first‐degree relatives of 252 probands with bipolar and unipolar affective disorders. Early onset probands (younger than 40 at onset) had more early onset relatives and a greater risk for affective disorder among their relatives than late onset probands (40 or older). This indicates that age‐of‐onset is a familial factor correlated with the liability to affective illness.

Genetic-linkage mapping of complex hereditary disorders to a whole-genome molecular-interaction network

Common hereditary neurodevelopmental disorders such as autism, bipolar disorder, and schizophrenia are most likely both genetically multifactorial and heterogeneous. Because of these characteristics traditional methods for genetic analysis fail when applied to such diseases. To address the problem we propose a novel probabilistic framework that combines the standard genetic linkage formalism with whole-genome molecular-interaction data to predict pathways or networks of interacting genes that contribute to common heritable disorders. We apply the model to three large genotype-phenotype data sets, identify a small number of significant candidate genes for autism (24), bipolar disorder (21), and schizophrenia (25), and predict a number of gene targets likely to be shared among the disorders.