Henriette Raventos

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

A genome scan meta-a nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (PSR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142–168 Mb) and 2q (103–134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119–152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for ‘aggregate’ genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16–33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

Neurocognitive Endophenotypes for Bipolar Disorder Identified in Multiplex Multigenerational Families

CONTEXT Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes. OBJECTIVE To adjudicate neurocognitive endophenotypes for bipolar disorder. DESIGN All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status. SETTING Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas. PARTICIPANTS Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia. MAIN OUTCOME MEASURE Neurocognitive test performance. RESULTS Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory. CONCLUSION This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.

A Novel Missense Mutation in the Transmembrane Domain of Neuregulin 1 is Associated with Schizophrenia

BACKGROUND Although genetic factors are known to play an important role in schizophrenia, the identification of genes involved in this disorder has remained elusive. The neuregulin 1 gene is among the few candidate genes to have been implicated in schizophrenia susceptibility in several populations. However, no causal mutations within this gene have been identified. METHODS In attempts to identify polymorphisms within the neuregulin 1 gene, we performed DNA sequencing using 12 subjects with a history of psychosis from the Central Valley of Costa Rica. DNA genotyping and association studies were then performed in an extended cohort of 142 affected individuals and their relatives from the same population. RESULTS We identified a novel missense mutation (Val to Leu) in exon 11, which codes for the transmembrane region of the neuregulin 1 protein. Association analysis by the Family Based Association Test (FBAT) revealed that this mutation is associated with psychosis (p = .0049) and schizophrenia (p = .0191) in this population. CONCLUSIONS We report the finding of a missense mutation in the neuregulin 1 gene associated with schizophrenia. Additional analyses of an independent sample as well as detailed functional studies should be performed to determine the relevance of this novel polymorphism to the pathophysiology of schizophrenia.

Arguments for the sake of endophenotypes: Examining common misconceptions about the use of endophenotypes in psychiatric genetics

Endophenotypes are measurable biomarkers that are correlated with an illness, at least in part, because of shared underlying genetic influences. Endophenotypes may improve our power to detect genes influencing risk of illness by being genetically simpler, closer to the level of gene action, and with larger genetic effect sizes or by providing added statistical power through their ability to quantitatively rank people within diagnostic categories. Furthermore, they also provide insight into the mechanisms underlying illness and will be valuable in developing biologically‐based nosologies, through efforts such as RDoC, that seek to explain both the heterogeneity within current diagnostic categories and the overlapping clinical features between them. While neuroimaging, electrophysiological, and cognitive measures are currently most used in psychiatric genetic studies, researchers currently are attempting to identify candidate endophenotypes that are less genetically complex and potentially closer to the level of gene action, such as transcriptomic and proteomic phenotypes. Sifting through tens of thousands of such measures requires automated, high‐throughput ways of assessing, and ranking potential endophenotypes, such as the Endophenotype Ranking Value. However, despite the potential utility of endophenotypes for gene characterization and discovery, there is considerable resistance to endophenotypic approaches in psychiatry. In this review, we address and clarify some of the common issues associated with the usage of endophenotypes in the psychiatric genetics community.

Adjudicating neurocognitive endophenotypes for schizophrenia.

Although genetic influences on schizophrenia are well established, localization of the genes responsible for this illness has proven extremely difficult. Given evidence that genes predisposing to schizophrenia may be transmitted without expression of the clinical phenotype, efforts have focused on developing endophenotypes. While several neuropsychological measures have been proposed to be endophenotypes, few studies have systematically assessed batteries of neurocognitive tests to determine which tests are most sensitive to liability for the illness. Two hundred sixty‐nine Latino individuals were administered a standard neuropsychological battery. Two hundred fourteen of these were members of families with at least two siblings diagnosed with schizophrenia or schizoaffective disorder. The remaining were community controls without history of major psychiatric illness. Neurocognitive measures found to be heritable were entered into analyses designed to determine which tests covary with the degree of genetic relationship to affected individuals. Although five measures were found to uniquely model genetic liability for schizophrenia, digit symbol coding was the most sensitive. To assess the specificity of these endophenotypes, performance on these measures were compared to family members with bipolar and unipolar affective disorders. These markers clearly distinguished between individuals with psychotic illnesses and those with major depression. As measures contributed uniquely to discriminate individuals at varying risk for schizophrenia, our findings imply multiple independently inherited elements to the liability for the illness. We present a practical model for adjudicating endophenotypes and determining which measures are best suited for use in linkage analyses.

Cannabinoid Receptor 1 Gene (CNR1) and Susceptibility to a Quantitative Phenotype for Hebephrenic Schizophrenia

Functional alterations of components of the endogenous cannabinoid system, in particular of the cannabinoid receptor 1 protein (CB1), are hypothetical contributors to many of the symptoms seen in schizophrenia. Variants within the cannabinoid receptor 1 gene (CNR1) have been shown to be directly associated with the hebephrenic form of schizophrenia in a Japanese population. This finding, however, has yet to be replicated. In the present study we sought to study the same (AAT)n‐repeat microsatellite of the CNR1 gene which showed association to hebephrenic schizophrenia in Japan, and to investigate whether this microsatellite showed association to a hebephrenic type of schizophrenia in a family‐based association study in a population of the Central Valley of Costa Rica. The Lifetime Dimensions of Psychosis Scale and a best estimate consensus process were utilized to identify subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for “hebephrenia.” Using the Family Based Association Test we found association of these hebephrenic subjects and the (AAT)n‐repeat marker of the CNR1 (multi‐allelic P = 0.0368). Our hypothesis that an association with the (AAT)n‐repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. Schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid‐induced psychosis. The current finding points to the possibility of different genetic and pathophysiologic mechanisms underlying different types of schizophrenia.

In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation

Neuregulin 1 (NRG1) has been implicated in several disorders including breast cancer, multiple sclerosis, and schizophrenia. Also, recent evidence suggests that NRG1 may play a role in regulation of inflammation and immune system response. We therefore hypothesized that a schizophrenia-associated missense mutation (valine to leucine) we identified within the transmembrane region of NRG1 would also be linked to immune dysregulation. We used plasma samples from families carrying the mutation to measure levels of antibodies to 41 autoimmune markers and six cytokines (IL-1b, IL-6, IL-10, IL-8, IL-12p70, and TNF-α) and used these levels as quantitative traits to evaluate association with the NRG1 mutation, using FBAT. Next, we used Epstein–Barr virus-transformed B cells from heterozygous mutation carriers and wild-type individuals to evaluate protein and mRNA cytokine expression in vitro using quantitative PCR and ELISA assays. In vivo, increased levels of 25 autoimmune markers as well as elevated levels of cytokines were significantly associated with the NRG1 mutation. In vitro, we observed a significant increase in protein secretion levels of IL-6, TNF-α, and IL-8 in mutation carriers compared with controls. At the mRNA level, we observed a significant increase in IL-6 expression, while IL-4 levels appeared to be down-regulated in heterozygous individuals compared with wild-type controls. This is the first report of association of a NRG1 mutation with immune dysregulation. This study could contribute towards understanding the role of NRG1 in the pathogenesis of schizophrenia and other disorders in which inflammation plays an important role.

Evidence of genetic overlap of schizophrenia and bipolar disorder: Linkage disequilibrium analysis of chromosome 18 in the Costa Rican population

The long‐standing concept that schizophrenia (SC) and bipolar disorder (BP) represent two distinct illnesses has been recently challenged by findings of overlap of genetic susceptibility loci for these two diseases. We report here the results of a linkage disequilibrium (LD) analysis of chromosome 18 utilizing subjects with SC from the Central Valley of Costa Rica. Evidence of association (P < 0.05) was obtained in three chromosomal regions: 18p11.31 (D18S63), 18q12.3 (D18S474), and 18q22.3‐qter (D18S1161, D18S70), all of which overlap or are in close proximity with loci previously shown to be in LD with BP, type I in this population. Since both the SC and bipolar samples contained cases with a history of mania and almost all cases of SC and BP had a history of psychosis, we performed an alternative phenotyping strategy to determine whether presence or absence of mania, in the context of psychosis, would yield distinct linkage patterns along chromosome 18. To address this issue, a cohort of psychotic patients (including a range of DSMIV diagnoses) was divided into two groups based on the presence or absence of mania. Regions that showed association with SC showed segregation of association when the sample was stratified by history of mania. Our results are compared with previous genetic studies of susceptibility to SC or BP, in Costa Rica as well as in other populations. This study illustrates the importance of detailed phenotype analysis in the search for susceptibility genes influencing complex psychiatric disorders in isolated populations and suggests that subdivision of psychoses by presence or absence of past mania syndromes may be useful to define genetic subtypes of chronic psychotic illness.

Genetic studies of neuropsychiatric disorders in Costa Rica: a model for the use of isolated populations.

The importance of genetics in understanding the etiology of mental illness has become increasingly clear in recent years, as more evidence has mounted that almost all neuropsychiatric disorders have a genetic component. It has also become clear, however, that these disorders are etiologically complex, and multiple genetic and environmental factors contribute to their makeup. So far, traditional linkage mapping studies have not definitively identified specific disease genes for neuropsychiatric disorders, although some potential candidates have been identified via these methods (e.g. the dysbindin gene in schizophrenia; Straub et al., 2002; Schwab et al., 2003). For this reason, alternative approaches are being attempted, including studies in genetically isolated populations. Because isolated populations have a high degree of genetic homogeneity, their use may simplify the process of identifying disease genes in disorders where multiple genes may play a role. Several areas of Latin America contain genetically isolated populations that are well suited for the study of neuropsychiatric disorders. Genetic studies of several major psychiatric illnesses, including bipolar disorder, major depression, schizophrenia, Tourette Syndrome, alcohol dependence, attention deficit hyperactivity disorder, and obsessive–compulsive disorder, are currently underway in these regions. In this paper we highlight the studies currently being conducted by our groups in the Central Valley of Costa Rica to illustrate the potential advantages of this population for genetic studies.

Association analyses of the neuregulin 1 gene with schizophrenia and manic psychosis in a Hispanic population

Objective:  This study used the population of the Central Valley of Costa Rica (CVCR) and phenotyping strategies alternative to DSMIV classifications to investigate the association of neuregulin 1 with schizophrenia.