The ascertainment of multiplex schizophrenia pedigrees from Daghestan genetic isolates (Northern Caucasus, Russia)

This article describes the preliminary ascertainment of multiplex schizophrenia pedigrees from the isolated mountain region of Daghestan (Northern Caucasus, Russia). Daghestan has a population of two million people and contains 26 aboriginal ethnic groups. Many of the ethnic groups reside in remote mountain villages that can be classified as 'primary isolates'. Prolonged reproductive isolation and severe environmental conditions in the highlands have created diverse, genetically isolated ethnic populations in Daghestan. A number of the isolates in this region contain large extended multiplex schizophrenia pedigrees that are ideal for genetic analyses. During summer expeditions of 1996 and 1997, 14 separate large multiplex schizophrenia pedigrees were ascertained from 14 different mountain villages. Of the 14 kindreds, one had 50 schizophrenic cases available for ascertainment, one had 32, and another had 24. Seven of the remaining pedigrees had between 11 and 23 living cases. Within the kindreds, the number of males with chronic schizophrenia was at least twice that of females. The average age of onset of schizophrenia is 21.2 years for offspring of consanguineous marriages and 17.4 years for offspring of nonconsanguineous marriages (P = 0.033). Although the pedigrees ascertained from the remote mountain villages may not be representative of the general population, they are unique kindreds for mapping schizophrenia susceptibility genes.     

Turning point in the design of linkage studies of schizophrenia

Despite extensive genomic scans, linkage studies of multiplex pedigrees have been unable to produce replicable evidence of genes predisposing to schizophrenia. This indicates that it is unlikely that a single gene accounts for a majority of cases of schizophrenia, even in multiplex pedigrees. It is most likely that schizophrenia is caused by the nonlinear interaction of multiple genetic and environmental factors influencing brain development and function. This conclusion has strong implications for the design of linkage and association studies. Recently designed linkage studies involve several improvements to deal with extensive locus heterogeneity and multiplicative interaction. These improvements include much larger samples of pedigrees, systematic ascertainment and sequential extension rules, and standardized procedures at multiple sites to facilitate collaboration and replication. Future improvements are likely to require advances in the assessment of clinical and neurobiological variability in multiplex pedigrees, more systematic environmental assessment, and advances in analytic methods to deal with multiplicative interaction. Rather than focusing only on schizophrenia as one or more discrete disorders, future linkage efforts should also consider the etiology of individual clinical syndromes or dimensional components of risk that interact to cause the complex pattern of syndromal comorbidity observed within schizophrenics and their families. © 1994 Wiley-Liss, Inc.     

Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau,Micronesia

Spatial working memory deficits associated with dorsolateral prefrontal dysfunction have been found in Caucasian samples of schizophrenia patients and their first-degree relatives. This study evaluated spatial working memory function in affected and unaffected members of multiplex schizophrenia families from the Republic of Palau to determine whether the spatial working memory deficits associated with schizophrenia extend to this non-Caucasian population. Palau is an isolated island nation in Micronesia with an elevated prevalence of schizophrenia and an aggregation of cases in large multigenerational families. Our objective was to evaluate the potential for spatial working memory function to serve as one of multiple endophenotypes in a genetic linkage study of these Palauan schizophrenia families. A spatial delayed response task requiring resistance to distraction and a sensorimotor control task were used to assess spatial working memory in 32 schizophrenia patients, 28 of their healthy first-degree relatives, and 19 normal control subjects. Schizophrenia patients and their relatives were significantly less accurate than normal control subjects on the spatial delayed response task but not on the sensorimotor control task. On both tasks, patients and relatives were slower to respond than the normal controls. There were no age or gender effects on accuracy, and working memory performance in schizophrenia patients was not significantly correlated with medication dosage. In summary, spatial working memory deficits that have been found in Caucasian schizophrenia patients and relatives were confirmed in this isolated Pacific Island family sample. These results suggest that spatial working memory deficits may be a potentially useful addition to the endophenotypic characterization of family members to be used in a comprehensive genome wide linkage analysis of these Palauan families.     

Analysis of epistasis in linked regions in the Irish study of high‐density schizophrenia families

Epistasis may be important in the etiology of schizophrenia. Analysis of epistasis has been important in the positional cloning of a gene involved in the etiology of type II diabetes mellitus. We investigated the importance of epistasis among six linked regions in 268 multiplex pedigrees in the Irish Study of High‐Density Schizophrenia Families (ISHDSF) by computing pairwise correlations between nonparametric linkage scores for narrow, intermediate, and broad diagnostic definitions. The linked regions were on chromosomes 2, 4, 5, 6, 8, and 10. No correlation reached our a priori level of statistical significance. Using this statistical approach, we did not find evidence of important epistatic effects among these six regions in the ISHDSF. © 2001 Wiley‐Liss, Inc.     

Analysis of epistasis in linked regions in the Irish study of high-density schizophrenia families

Epistasis may be important in the etiology of schizophrenia. Analysis of epistasis has been important in the positional cloning of a gene involved in the etiology of type II diabetes mellitus. We investigated the importance of epistasis among six linked regions in 268 multiplex pedigrees in the Irish Study of High-Density Schizophrenia Families (ISHDSF) by computing pairwise correlations between nonparametric linkage scores for narrow, intermediate, and broad diagnostic definitions. The linked regions were on chromosomes 2, 4, 5, 6, 8, and 10. No correlation reached our a priori level of statistical significance. Using this statistical approach, we did not find evidence of important epistatic effects among these six regions in the ISHDSF.     

The recognition of facial affect in autistic and schizophrenic subjects and their first-degree relatives

BACKGROUND: Autism and schizophrenia are considered to be substantially influenced by genetic factors. The endophenotype of both disorders probably also includes deficits in affect perception. The objective of this study was to examine the capacity to detect facially expressed emotion in autistic and schizophrenic subjects, their parents and siblings. METHOD: Thirty-five subjects with autism and 102 of their relatives, 21 schizophrenic subjects and 46 relatives from simplex (one child affected) and multiplex (more than one child affected) families, as well as an unaffected control sample consisting of 22 probands completed a 50-item computer-based test to assess the ability to recognize basic emotions. RESULTS: The autistic subjects showed a poorer performance on the facial recognition test than did the schizophrenic and the unaffected individuals. In addition, there was a tendency for subjects from multiplex families with autistic loading to score lower on the test than individuals from simplex families with autistic loading. Schizophrenic subjects and their relatives as well as siblings and parents of autistic subjects did not differ from the sample of unaffected subjects in their ability to judge facial affect. CONCLUSIONS: Findings corroborate the assumption that emotion detection deficits are part of the endophenotype of autism. In families with autistic children, the extent of facial recognition deficits probably indexes an elevation in familial burden. It seems unlikely that problems in emotion perception form a consistent part of the endophenotype of schizophrenia or the broader phenotype in relatives of patients with psychosis or autism.     

Genetic epidemiological study of schizophrenia in Palau, Micronesia: prevalence and familiality

We are studying the genetic etiology of schizophrenia in the Republic of Palau, a remote island nation in Micronesia that has been geographically and ethnically isolated for approximately 2,000 years. The first epidemiological phase sought to estimate the lifetime prevalence of schizophrenia and evaluate the familiality of the illness based on complete ascertainment of cases and families segregating schizophrenia. A total of 160 strictly defined cases of schizophrenia were ascertained in a population of 13,750 adults who were 15 years of age and older. The lifetime prevalence of strictly defined schizophrenia in Palau was 1.99% overall and 2.77% in males vs. 1.24% in females. This greater than 2:1 male-to-female risk ratio for schizophrenia was accompanied by an earlier mean age of onset for males (23.3 years) than for females (27.5 years). These 160 cases of strict schizophrenia represent 59 separate families each identified by a single common founder. Eleven of these families have 5 to 14 cases and represent nearly half of the strict schizophrenia cases in Palau. Although schizophrenia is clearly aggregating in these 11 families, cases are distributed sparsely throughout the large sibships. In the entire sample of 160 cases of strict schizophrenia, there were only 11 sib-pairs and 2 sib-trios. When a family was defined to include third-degree relatives, only 11 cases (6.9%) were nonfamilial. The majority of the ascertained cases can be linked together into extended pedigrees with complex multilineal inheritance patterns. These intricately interconnected families may pose challenges for traditional linkage techniques. However, these Palauan families represent a valuable resource for studying the genetic etiology of schizophrenia because there may be fewer susceptibility genes for schizophrenia in this genetic isolate than in the heterogeneous populations that are common throughout the world today.     

Admixture analysis of smooth pursuit eye movements in probands with schizophrenia and their relatives suggests gain and leading saccades are potential endophenotypes

Abnormalities during a smooth pursuit eye movement task (SPEM) are common in schizophrenic patients and their relatives. This study assessed various components of SPEM performance in first-degree unaffected relatives of schizophrenic patients. One hundred individuals with schizophrenia, 137 unaffected first-degree relatives, and 69 normal controls completed a 16.7 degrees/s SPEM task. Smooth pursuit gain, catch-up saccades (CUS), large anticipatory saccades, and leading saccades (LS) were identified. Groups were compared with parametric and admixture analyses. Schizophrenic patients performed more poorly than unaffected relatives and normals on gain, CUS, and LS. Unaffected relatives were more frequently impaired than normals only on gain and LS. Relatives of childhood-onset and adult-onset probands had similar impairments. Gain and frequency of leading saccades may be genetic endophenotypes in childhood-onset and adult-onset schizophrenia.     

Heritability and number of quantitative trait loci of neurocognitive functions in families with schizophrenia

Despite evidence for several chromosomal loci linked to schizophrenia, no susceptibility genes have been identified for the disorder. Using quantitative measures of phenotypic affection in place of clinical diagnostic categories or dichotomous classification of the affection status may be more effective in searching for susceptibility genes. Neurocognitive traits have been suggested as putative quantitative endophenotypes of the disorder, but their heritability estimates are not well known. We investigated the heritability of working memory, verbal declarative memory and its different components, and both verbal and visual ability functions in schizophrenia families with a well-ascertained pedigree structure. We also estimated the number of quantitative trait loci (QTLs) contributing to these neurocognitive functions. Additive genetic heritability of the neurocognitive functions was estimated in a sample of schizophrenia patients and their first-degree relatives (N = 264) from an isolated geographical subregion in Finland. The number of QTLs was analyzed using Markov chain Monte Carlo segregation analysis. Significant heritabilities were found in working memory and ability functions. Furthermore, the working memory functions revealed the most restricted number of QTLs. The mean numbers of loci for verbal and visual working memory were 1.2 and 1.0, respectively, with corresponding posterior probabilities of 73% and 70% for at least one locus. In declarative memory variables, the number of loci was more dispersed. Our results suggest that neurocognitive measures, particularly working memory, may provide valid quantitative phenotypic traits for linkage analyses searching predisposing genes for schizophrenia.     

Molecular breakpoint analysis and relevance of variable mosaicism in a woman with short stature,primary amenorrhea,unilateral gonadoblastoma,and a 46,X,del(Y)(q11)/45,X karyotype

An impressive LOD score of 6.5 has recently been reported for schizophrenia on chromosome 1q21-22 in large families from eastern Canada [Brzustowicz et al., 2000: Science 288:678-682]. We did not reproduce such a finding in large pedigrees of eastern Québec based on seven markers spanning the 1p13-1q22 region and using both the models and phenotypes of Brzustowicz et al. and those used in our ongoing genome scan in 21 large French Canadian families. There was no significant total LOD scores in that chromosomal region (a maximum of 0.57) either for schizophrenia or bipolar disorders, nor any signal in individual large pedigrees. However, the samples of Brzustowicz et al. and ours differed in terms of their origins, the latter being of French ancestry and the former of Celtic and German descent. Population difference, genetic heterogeneity, and differences in ascertainment might explain the lack of replication. The result reported by Brzustowicz et al. cannot be discarded and should probably be considered as a susceptibility locus for a subset of the schizophrenic population.     

Relationship between schizoaffective illness and affective disorders or schizophrania: Morbidity risk and genetic transmission

Schizoaffective illness has either been linked to schizophrenia and to affective disorders, or it has been considered to be a separate entity. Family and linkage studies can provide data regarding genetic factors in the aetiology of schizoaffective illness. Morbidity risks for affective illnesses and schizophrenia were estimated in the first-degree relatives of schizoaffective probands as compared to matched controls (bipolars, unipolars and schizophrenics). Linkage studies with X-chromosome markers (protanopia and deuteranopia) were also performed in informative families. Our genetic results indicate that schizoaffective illness is a heterogeneous entity. This syndrome appears to be primarily related to the affective disorders, but there may be a subgroup linked to the schizophrenic spectrum disorders. Our studies also indicate that some schizoaffective syndromes may be transmitted through the X-chromosome, a pattern previously demostrated in some families with bipolar manic-depressive illness.     

Investigation of linkage and association/linkage disequilibrium of HLA A‐, DQA1‐, DQB1‐, and DRB1‐alleles in 69 sib‐pair‐ and 89 trio‐families with schizophrenia

The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib‐pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA‐ DRB1*11 (chi‐square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301—DQA1*501—DRB1*11 (chi‐square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31. © 2002 Wiley‐Liss, Inc.     

Association and expression study of synapsin III and schizophrenia

The synapsin III gene, SYN3, which belongs to the family of synaptic vesicle-associated proteins, has been implicated in the modulation of neurotransmitter release and in synaptogenesis, suggesting a potential role in several neuropsychiatric diseases. The human SYN3 gene is located on chromosome 22q12-13, a candidate region implicated in previous linkage studies of schizophrenia. However, association studies of SYN3 and schizophrenia have produced inconsistent results. In this study, four SYN3 SNPs (rs133945 (−631 C > G), rs133946 (−196 G > A), rs9862 and rs1056484) were tested in three sets of totally 3759 samples that comprise 655 affected subjects and 626 controls in the Irish Case-Control Study of Schizophrenia (ICCSS), 1350 samples incorporating 273 pedigrees in the Irish Study of High Density Schizophrenia Families (ISHDSF), and 564 unrelated schizophrenia patients and 564 healthy individuals in a Chinese case-control sample. The expression levels of SYN3 in schizophrenic patients and unaffected controls were compared using postmortem brain cDNAs provided by the Stanley Medical Research Institute (SMRI). There was no significant association in either the Irish or Chinese case-control samples, nor in the combined samples. Consistent with this finding, we did not find any significant difference in allele or haplotype frequencies when we used the pedigree disequilibrium test to analyze the Irish family sample. In the expression studies, no significant difference (p = 0.507) was observed between patients and controls. Both the association studies and expression studies didn’t support a major role for SYN3 in the susceptibility of schizophrenia in Irish and Chinese populations.     

Measuring liability for schizophrenia using optimized antisaccade stimulus parameters

The ability to identify unaffected gene carriers within families may be crucial to the success of schizophrenia genetics studies. Data collected from three family samples (N = 365) demonstrated that poor antisaccade performance is an exceptionally promising indicator of liability for schizophrenia. A particular antisaccade task version provides large separations (5-6 sigma) between proband and normal groups. Poor antisaccade performance alone correctly identified 70% of patients in California, Utah, and Micronesia schizophrenia samples. Twenty-five to 50% of these patients' nonpsychotic first-degree relatives also had poor antisaccade performance, yielding risk ratios around 20:1 for simplex and 50:1 for multiplex schizophrenia families. Poor antisaccade performance is associated with dorsolateral prefrontal cortex pathology, suggesting that dysfunction of this circuitry also may predispose individuals to developing this disease.     

Exclusion of linkage between schizophrenia and the gene encoding a neutral amino acid glutamate/aspartate transporter,SLC1A5

An abnormality in glutamatergic function has been hypothesized as being of etiological importance in schizophrenia. Twenty-three multiplex English and Icelandic schizophrenia families were genotyped with a polymorphic dinucleotide repeat sequence in the 3′-untranslated region of the glutamate/aspartate transporter gene called SLC1A5. Using the lod and a model-free method of linkage analysis (MFLINK), no evidence of linkage between SLC1A5 and schizophrenia was found. Our results do not support the hypothesis that SLC1A5 gene mutations or allelic variants provide a major gene contribution to the etiology of schizophrenia. However, because of the likelihood of heterogeneity of linkage in schizophrenia, there is a case for testing other pedigrees for linkage to the SLC1A5 locus. The SLC1A5 locus is one of a complex family of genes encoding neutral amino acid transporter proteins and the genetic relation between these other loci and schizophrenia has not yet been established. Am. J. Med. Genet. 74:50–52, 1997. © 1997 Wiley-Liss, Inc.     

Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau,Micronesia

Spatial working memory deficits associated with dorsolateral prefrontal dysfunction have been found in Caucasian samples of schizophrenia patients and their first‐degree relatives. This study evaluated spatial working memory function in affected and unaffected members of multiplex schizophrenia families from the Republic of Palau to determine whether the spatial working memory deficits associated with schizophrenia extend to this non‐Caucasian population. Palau is an isolated island nation in Micronesia with an elevated prevalence of schizophrenia and an aggregation of cases in large multigenerational families. Our objective was to evaluate the potential for spatial working memory function to serve as one of multiple endophenotypes in a genetic linkage study of these Palauan schizophrenia families. A spatial delayed response task requiring resistance to distraction and a sensorimotor control task were used to assess spatial working memory in 32 schizophrenia patients, 28 of their healthy first‐degree relatives, and 19 normal control subjects. Schizophrenia patients and their relatives were significantly less accurate than normal control subjects on the spatial delayed response task but not on the sensorimotor control task. On both tasks, patients and relatives were slower to respond than the normal controls. There were no age or gender effects on accuracy, and working memory performance in schizophrenia patients was not significantly correlated with medication dosage. In summary, spatial working memory deficits that have been found in Caucasian schizophrenia patients and relatives were confirmed in this isolated Pacific Island family sample. These results suggest that spatial working memory deficits may be a potentially useful addition to the endophenotypic characterization of family members to be used in a comprehensive genome wide linkage analysis of these Palauan families. © 2002 Wiley‐Liss, Inc.     

Neurocognition in youth and young adults under age 30 at familial risk for schizophrenia: A quantitative and qualitative review

Introduction. Neurocognitive dysfunction is a central feature of schizophrenia and is observed during all phases of the illness. Because schizophrenia is known to run in families, studying neurocognitive function in first-degree, nonpsychotic relatives has been a widely utilised strategy for almost 50 years for understanding presumed “genetic risk”. Studying nonpsychotic relatives (“familial high-risk”, or FHR) allows for identification of cognitive vulnerability markers independent of confounds associated with psychosis.

Methods. Prior meta-analyses have elucidated the level and pattern of cognitive deficits in the premorbid, prodromal, and postonset periods of psychosis, and in relatives regardless of age. However, no prior quantitative analyses have specifically focused on studies of young first-degree relatives of individuals with schizophrenia who have not passed through the peak age illness risk (<age 30). The English language literature of neuropsychological studies of first-degree relatives for schizophrenia was identified up to 15 May 2011.

Results. From 33 studies, 28 studies met our criteria for quantitative review, utilising >70 individual tests and 250 variables.

Conclusions. In general, young FHR individuals demonstrated deficits with a moderate level of severity compared with healthy controls. The largest average effect sizes (ESs), based on tests given in at least three independent studies, were on estimates of Full Scale IQ (d= ?0.777), followed by Vocabulary (d= ?0.749) and single word reading tests (d= ?0.698) (often used as estimates of IQ). Measures of declarative memory, sustained attention, working memory and others had more modest ESs. Deficits were milder than in established schizophrenia, but often as severe as in clinical high-risk or putatively prodromal participants and in older relatives examined in prior meta-analyses. Additionally, while assessed from a more limited literature, youth at FHR for schizophrenia tended to show worse neurocognitive functioning than those at FHR for affective psychosis. This suggests that genetic risk for schizophrenia as reflected in a positive FHR carries an especially heavy impact on cognitive ability.     

Genome-wide search for schizophrenia susceptibility loci: The NIMH genetics initiative and millennium consortium

Schizophrenia has a complex pattern of inheritance, indicative of interactions among multiple genes and environmental factors. The detection and replication of specific susceptibility loci for such complex disorders are facilitated by the availability of large samples of affected sib pairs and their nuclear families, along with standardized assessment and systematic ascertainment procedures. The NIMH Genetics Initiative on Schizophrenia, a multisite collaborative study, was established as a national resource with a centralized clinical data base and cell repository. The Millennium Schizophrenia Consortium has completed a genome-wide scan to detect susceptibility loci for schizophrenia in 244 individuals from the nuclear families of 92 independent pairs of schizophrenic sibs ascertained by the NIMH Genetics Initiative. The 459 marker loci used in the scan were spaced at 10-cM intervals on average. Individuals of African descent were higher than those of European descent in their average heterozygosity (79% vs. 76%, P < .0001) and number of alleles per marker (9.2 vs. 8.4, P < .0001). Also, the allele frequencies of 73% of the marker loci differed significantly (P < .01) between individuals of European and African ancestry. However, regardless of ethnic background, this sample was largely comprised of schizophrenics with more than a decade of psychosis associated with pervasive social and occupational impairment. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:275–281, 1998. © 1998 Wiley-Liss, Inc.     

Recurrence risk to offspring in extended multiplex schizophrenia pedigrees from a Pacific Island isolate.

Genetic transmission plays a major role in the pathogenesis of schizophrenia. Family, twin, and adoption studies have consistently shown that risks in relatives are many times greater than the general population risk of approximately 1%. McGue, Gottesman, and Rao (1983; Am J Hum Genet 35:1161-1178) calculated risk estimates of 12.8% for offspring and 3.5% for nieces/nephews of schizophrenia patients based on a large data set of Western European families. The present study evaluated corresponding risk levels in Palau, an isolated population in Micronesia where the prevalence of narrowly (broadly) defined schizophrenia is 1.99% (2.67%) and cases cluster in extended pedigrees, 20 of which contain 80% of affected individuals. We hypothesized that offspring in these extended families would have a higher risk for schizophrenia than offspring in smaller schizophrenia pedigrees from more genetically heterogeneous populations. RDC diagnostic data based on complete ascertainment of cases and their families covering the past two generations were used to quantify empirical recurrence risks in the offspring and nieces/nephews of Palauan schizophrenia patients. Risks to 1st- and 2nd-degree offspring were approximately double the rates found in the smaller Western European families: 23.4% in the offspring of an affected parent, 6.4% in offspring with one affected aunt/uncle, and 15.0% in offspring with two or more affected aunts/uncles. Recurrence rates in offspring of an affected parent were 1.6 times higher in males (27.9%) than in females (17.7%). The high risk levels we found in Palauan offspring reflect the elevated population prevalence, strong familial aggregation, and multi-lineal transmission pattern of schizophrenia in Palau.     

No evidence for linkage between schizophrenia and markers at chromosome 15q13-14

Freedman et al. [1997: Proc Natl Acad Sci USA 94:587-592] reported linkage in nine multiplex schizophrenia families to markers on chromosome 15, using impaired neuronal inhibition to repeated auditory stimuli (P50), a neurophysiological deficit associated with schizophrenia, as the phenotype. The highest LOD score obtained (5.3 at theta = 0) was for marker D15S1360 mapped to chromosome 15q13-14, less than 120 kb from the alpha7-nicotinic receptor (CHRNA7) gene. The study also reported a small positive LOD score for D15S1360 when examined for linkage to the schizophrenia phenotype. Following these findings, we examined three polymorphic markers (D15S1360, L76630, and ACTC) on chromosome 15q13-14 near the CHRNA7 gene for linkage to schizophrenia, using 54 pedigrees from an independent study. Alleles for these three markers were genotyped and analyzed using parametric and nonparametric methods. No LOD score above 1.00 was obtained for any marker, and affected sib-pair analysis likewise showed no evidence for linkage. We conclude that in our families the region around the CHRNA7 locus does not contain a major locus for susceptibility to schizophrenia.