Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q.

It is widely accepted that founder populations hold promise for mapping loci for complex traits. However, the outcome of these mapping efforts will most likely depend on the individual demographic characteristics and historical circumstances surrounding the founding of a given genetic isolate. The 'ideal' features of a founder population are currently unknown. The Micronesian islandic population of Kosrae, one of the four islands comprising the Federated States of Micronesia (FSM), was founded by a small number of settlers and went through a secondary genetic 'bottleneck' in the mid-19th century. The potential for reduced etiological (genetic and environmental) heterogeneity, as well as the opportunity to ascertain extended and statistically powerful pedigrees makes the Kosraen population attractive for mapping schizophrenia susceptibility genes. Our exhaustive case ascertainment from this islandic population identified 32 patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Three of these were siblings in one nuclear family, and 27 were from a single large and complex schizophrenia kindred that includes a total of 251 individuals. One of the most startling findings in our ascertained sample was the great difference in male and female disease rates. A genome-wide scan provided initial suggestive evidence for linkage to markers on chromosomes 1, 2, 3, 7, 13, 15, 19, and X. Follow-up multipoint analyses gave additional support for a region on 2q37 that includes a schizophrenia locus previously identified in another small genetic isolate, with a well-established recent genealogical history and a small number of founders, located on the eastern border of Finland. In addition to providing further support for a schizophrenia susceptibility locus at 2q37, our results highlight the analytic challenges associated with extremely large and complex pedigrees, as well as the limitations associated with genetic studies of complex traits in small islandic populations.

Early, non-psychotic deviant behavior in schizophrenia: a possible endophenotypic marker for genetic studies.

Early non-psychotic deviance occurs in some, but not all, pre-schizophrenic patients and has been linked to the later course of the disorder, suggesting its relationship with the schizophrenia syndrome. However, early deviance has rarely been explored as an endophenotypic marker in large samples of schizophrenic patients. We characterized the early childhood behavior and syndrome history of 205 adults with DSM-IV schizophrenia. Sixty percent of our sample had poor socialization, extreme fears/chronic sadness, and/or attention impairment/learning disabilities beginning before age 10. The remaining 40% were without behavioral difficulties until the onset of schizophrenia. Logistic regression analyses suggested that the risk of syndrome onset before age 17 was 2.5 times more likely among patients with poor socialization beginning before age 10. Schizoaffective disorder was 3.75 times greater among patients with extreme fears/chronic sadness in childhood, and schizophrenic patients with early attention impairment/learning disabilities were 2 times more likely to have a 1 degrees, 2 degrees or 3 degrees relative with schizophrenia. We concluded that early deviant behavior indicated a distinct subgroup of patients, and was linked to syndrome characteristics specifically relevant to genetic studies, in particular age at onset and family history of schizophrenia. Since early syndrome onset has been associated with specific genetic anomalies in other complex neuropathologic disorders, it may prove valuable to regard these early deviant behaviors as an indicator of early syndrome onset for future genetic studies of schizophrenia.

Epidemiology and factor analysis of obesity, type II diabetes, hypertension, and dyslipidemia (syndrome X) on the Island of Kosrae, Federated States of Micronesia.

OBJECTIVES: Obesity, type II diabetes, hypertension, and dyslipidemia are major causes of morbidity and mortality throughout the world. Though these disorders often cluster in individuals and families and are collectively known as syndrome X, the basis for this aggregation is not well understood. To further understand the pathogenesis of syndrome X, a comprehensive epidemiological study was undertaken on the Pacific Island of Kosrae, Federated States of Micronesia (FSM). METHODS: The entire adult (>20 years of age) population of Kosrae underwent a clinical evaluation that included a questionnaire that noted the participants' sex, family data including listing of biological parents, siblings, and children, smoking status, village of residence, age and health status. The medical evaluation included: anthropometric measures (weight, height, waist, hip), serum chemistries (leptin, fasting blood sugar (FBS), insulin, total cholesterol (TC), triglycerides (TG), and apolipoproteins B and A-I (apo B and apo A-I) and blood pressure (BP) measurements. RESULTS: Obesity (BMI >/=35) was found in 24%, diabetes (FBS >/=126 or 2-hour oral glucose tolerance test >/=200) in 12%, hypertension (SBP >/=140 or DBP >/=90) in 17%, and dyslipidemia (TC >/=240 or TG >/=200 or apo B >/=120 or apo A-I

Phenotypic differences in early- and late-onset obsessive-compulsive disorder.

Early-onset forms of many medical diseases have been associated with specific genetic anomalies. To assess the potential marker value of onset age in obsessive-compulsive disorder (OCD), we examined and compared the phenotypic characteristics of patients with early and later onset. The study sample included 38 children with DSM-IV OCD and 129 adults 19 years of age or older, 77 of whom reported OCD onset prior to age 18 and 52 of whom reported OCD onset at 18 years of age or older. DSM-IV diagnoses were ascertained for all subjects using an amended version of the Diagnostic Interview for Genetic Studies (DIGS). An initial comparison of children and adults with childhood onset revealed several differences, including an earlier onset of clinically significant symptoms without impairment and earlier onset of DSM-IV OCD, a higher frequency of learning disabilities, and fewer obsessions and compulsions among our child patients. For this reason, subsequent analyses included only adult patients with early and later OCD onset. Nonimpairing symptom onset prior to puberty, a relatively aggressive course, and a greater number of obsessions and compulsions unrelated to the amount of time in illness characterized early-onset OCD. Later-onset OCD was characterized by nonimpairing symptom onset during puberty, a static course, and relatively few obsessions and compulsions that were variably related to the amount of time in illness. We conclude that children with OCD and adults with childhood onset differ in their report of clinical characteristics and should be analyzed separately in studies concerning the phenotypic characteristics of OCD. Early- and late-onset forms of OCD appear to be characterized by phenotypic features that have important neurobiologic and perhaps genetic implications.

Evidence of a schizotypy subtype in OCD.

OCD patients represent a heterogeneous mix of clinical phenotypes, likely reflecting a wide range of genetic vulnerabilities. In other medical illnesses, neurobiologically-based traits with a genetic component that are associated with the target disorder have been successfully used to detect patients with a specific genetic liability to disease. The overlap between symptoms of OCD and Schizophrenia suggested that schizotypal traits could have the potential to distinguish a relatively homogeneous subtype of OCD. We obtained schizotypy scores for 119 affected adult probands who met lifetime criteria for DSM-IV OCD. Five subscales from the Structured Interview of Schizotypy were used to assess ideas of reference, suspiciousness, magical thinking, illusions and psychotic-like thought. Selected for their obvious face validity with the cardinal signs of schizophrenia, Cronbach's alpha suggested that these subscales also provided a reliable measure of positive sign schizotypy (0.83). Fifty percent of our OCD sample had mild to severe positive schizotypy signs. t- and chi2 tests of significance suggested seven variables that distinguished OCD patients with schizotypy, including earlier age of onset, greater number of comorbid diagnoses and increased rates of learning disability, aggressive and somatic obsessions and counting and arranging compulsions. Three of these seven variables, including learning disabilities, counting compulsions and history of specific phobia, significantly increased the odds of schizotypy among patients with lifetime OCD. These findings enhanced the validity of the schizotypy construct in OCD. Whether this schizotypy subtype can distinguish a subgroup of patients with relatively homogeneous genetic characteristics waits further investigation.

Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1-3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-methyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene modulating monoamine metabolism. METHODS: A sample of 110 nuclear OCD families was collected, and lifetime diagnoses were ascertained using the Diagnostic Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO genes, and allele inheritance was examined using the Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) test. RESULTS: We provide evidence supporting the previously reported sexually dimorphic association between low COMT enzymatic activity and OCD. We also provide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic activity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD probands with co-morbid MDD, who represent more than 50% of our male OCD sample. CONCLUSIONS: Our analysis indicates that variants of two genes modulating monoamine metabolism contribute significantly to OCD susceptibility. Most importantly, an unexpected sexually dimorphic pattern of genetic susceptibility to OCD is revealed and suggests the possibility that profound gender differences in genetic predisposition may exist not only for other OCD susceptibility genes, but for an array of other psychiatric disorders as well.

Homozygosity mapping of the Achromatopsia locus in the Pingelapese.

Achromatopsia, or total color blindness (also referred to as "rod monochromacy"), is a severe retinal disorder characterized clinically by an inability to distinguish colors, impaired visual acuity in daylight, photophobia, and nystagmus. Inherited as an autosomal recessive trait, achromatopsia is rare in the general population (1:20,000-1:50,000). Among the Pingelapese people of the Eastern Caroline Islands, however, the disorder occurs at an extremely high frequency, as recounted in Oliver Sacks's popular book The Island of the Colorblind: 4%-10% of this island population have the disorder and approximately 30% carry the gene. This extraordinary enrichment of the disease allele most likely resulted from a sharp reduction in population in the late 18th century, in the aftermath of a typhoon and subsequent geographic and cultural isolation. To obtain insights into the genetic basis of achromatopsia, as well as into the genetic history of this region of Micronesia, a genomewide search for linkage was performed in three Pingelapese kindreds with achromatopsia. A two-step search was used with a DNA pooling strategy, followed by genotyping of individual family members. Genetic markers that displayed a shift toward homozygosity in the affected DNA pool were used to genotype individual members of the kindreds, and an achromatopsia locus was identified on 8q21-q22. A maximal multipoint LOD score of 9.5 was observed with marker D8S1707. Homozygosity was seen for three adjacent markers (D8S275, D8S1119, and D8S1707), whereas recombination was observed with the flanking markers D8S1757 and D8S270, defining the outer boundaries of the disease-gene locus that spans a distance of <6.5cM.

The mutational status of p53 protein in gastric and esophageal adenocarcinoma cell lines predicts sensitivity to chemotherapeutic agents.

Resistance to chemotherapy remains a serious problem in the successful treatment of gastric and esophageal cancers. DNA-damaging agents alter levels of p53 protein in several cell types and it has been speculated that regulation of p53 can be involved in the resistance or sensitivity of cancer cells to some chemotherapeutic drugs, depending on whether cells have mutant or wild-type p53; however, little is known about the relationship of p53 to drug sensitivity in gastric/esophageal cancers. Here we have examined human gastric/esophageal adenocarcinoma cell lines for p53 mutational status, chemosensitivity to 5-fluorouracil, mitomycin C, and cis-dichlorodiammineplatinum(II), alteration in p53 levels following exposure of cells to these drugs, and the mechanisms involved in regulating p53 levels. Our results indicate that wild-type p53 protein levels increase after treatment with each of these drugs via either post-translational and/or translational mechanisms and that this increase in wild-type p53 appears to be required for effective chemotherapeutic growth control of gastric/esophageal adenocarcinoma cells. In contrast, gastric/esophageal cancer cells expressing either mutated p53 protein or no p53 protein are more resistant to the growth-inhibitory effects of these drugs, despite the fact that drug exposure can also increase mutant p53 levels by a translational mechanism. Thus, these data indicate that the mutational status of p53 is predictive of chemosensitivity of gastric and esophageal adenocarcinomas, and suggest a mechanism in which p53 protein contributes to the cellular response to chemotherapy.