Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds.

The age of onset of Huntington's disease (HD) is inversely correlated with the CAG length in the HD gene. The CAG repeat length accounts for 70% of the variability in HD age of onset. However, 90% of individuals worldwide with expanded alleles possess between 40 and 50 CAG repeat lengths in their HD gene. For these people, the size of their repeat only determines 44% of the variability in their age of onset. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. We analyzed the large Venezuelan kindreds in which the HD gene was originally identified. These kindreds offer greater analytic power than standard sib-pair designs. We developed novel pedigree-member selection procedures to maximize power. Using a 5,858-single-nucleotide-polymorphism marker panel, we performed a genomewide linkage analysis. We discovered two novel loci on chromosome 2. Chromosome 2p25 (logarithm of the odds ratio (LOD)=4.29) and 2q35 (LOD=3.39) may contain genes that modify age of onset. A third linkage peak on chromosome 6q22 (LOD=2.48) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggestive on chromosome 5 (LOD=3.31 at 5p14 and LOD=3.14 at 5q32). All these regions harbor candidate genes that are potential HD modifier genes. Finding these modifier genes can reveal accessible and promising new therapeutic pathways and targets to ameliorate and cure HD.

Wisconsin Card Sorting deficits in the offspring of schizophrenics in the New York High-Risk Project.

It has been suggested that performance on the Wisconsin Card Sorting Test (WCST) may be an indicator of vulnerability to schizophrenia. WCST deficits have been demonstrated in schizophrenic patients and their relatives, but not as yet in their offspring. This study aimed to further establish the indicator potential of WCST deficits by analyzing data collected as part of the New York High-Risk Project (NYHRP), a longitudinal study of attention, cognition and clinical functioning in the offspring of schizophrenic (HRSz, n=73), affective disordered (HRAff, n=61) and normal comparison (NC, n=120) parents. Parental Research Diagnostic Criteria diagnoses were established by semi-structured interview (SADS-L). WCST testing was carried out when offspring were in their mid-20s. HRSz subjects performed significantly more poorly on the WCST than HRAff and NC subjects. High-risk subjects who developed psychotic symptoms prior to or shortly after testing did not differ significantly from HRSz subjects who did not become ill. Thus, WCST performance in the offspring of schizophrenics resembles that of schizophrenic patients and may distinguish HRSz from offspring at risk for nonschizophrenic illness. WCST deficits may be a specific familial indicator of vulnerability, but appear not to distinguish between those subjects at risk for schizophrenia who do or do not become ill.

Thought disorder in offspring of schizophrenic parents: findings from the New York High-Risk Project.

The goal of the present analyses was to examine the hypothesis that mild forms of thought disorder (TD) may serve as an indicator of genetic liability for schizophrenia. A subset of 232 subjects drawn from the New York High-Risk Project was used to compare individuals at high risk for schizophrenia (ie, offspring of parents with schizophrenia; n = 63) with 2 groups of individuals at low risk for schizophrenia (ie, offspring of parents with affective disorder [n = 52] and offspring of psychiatrically normal parents [n = 117]). Subjects were administered the Rorschach Inkblot Test, and their responses were assessed according to the Thought Disorder Index (TDI). The high-risk offspring displayed significantly more TD than the other 2 groups, as shown by significantly higher TDI scores. Moreover, they had more deviant verbalizations, according to their significantly higher scores on a composite Idiosyncratic Verbalizations score. As expected, the offspring who developed psychosis produced more TD in adolescence than those who did not develop psychosis. In the sample as a whole, TD scores during late adolescence/early adulthood were positively associated with schizotypal features during mid-adulthood. These findings support the assertion that the presence of TD serves as an endophenotypic marker of a schizophrenia diathesis.

Interval-timing deficits in individuals at high risk for schizophrenia.

A duration-bisection procedure was used to study the effects of signal modality and divided attention on duration classification in participants at high genetic risk for schizophrenia (HrSz), major affective disorder (HrAff), and normal controls (NC). Participants learned short and long target durations during training and classified probe durations during test. All groups classified visual signals as shorter than equivalent duration auditory signals. However, the difference between auditory and visual signal classification was significantly larger for the HrSz group than for the NC group. We posit a model in which there is a clock rate difference between auditory and visual signals due to an attentional effect at the level of a mode switch that gates pulses into an accumulator. This attentionally mediated clock rate difference was larger for the HrSz participants than for the NC participants, resulting in a larger auditory/visual difference for the HrSz group.

Handedness in children of schizophrenic parents: data from three high-risk studies.

This is the first report of data analyses from a consortium of longitudinal genetic-risk studies on offspring of schizophrenic parents (CLOSSER) who were followed from birth or mid-childhood to their early 20's or considerably older ages. Three of the CLOSSER studies provide data to enable us to address long-persisting questions in the schizophrenia literature concerning possible atypicality of hand dominance associated with the illness. Handedness, used as a proxy for cerebral lateralization, is a topic of considerable importance because of its potential to reveal mechanisms in the underlying pathophysiology of schizophrenia. We examine agreement among the CLOSSER studies with respect to possible deviance in handedness in subjects with schizophrenic parents (high-risk individuals) and specifically in those who have gone on to develop adult schizophrenia, compared with other subjects of these studies. Possible developmental delay in age at lateralization is also considered.

PERSONALITY FEATURES AND DISORDER IN THE SUBJECTS IN THE NEW YORK HIGH-RISK PROJECT.

One hundred and seventy-five offspring of parents in two psychiatrically ill groups and of normal controls in the New York High-Risk Project (NYHRP) were assessed for Axis II personality traits and disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R). These offspring include: subjects at high risk for schizophrenia (HRSz, n = 48), all of whom have a parent with schizophrenic disorder; subjects at high risk for affective disorder (HRAff, n = 40), all of whom have a parent with affective disorder; and subjects at no increased risk for psychiatric illness (NC, n = 87), whose parents are psychiatrically normal. The trained interviewers, who administered a standardized direct interview, were blind to parental clinical status and to previous clinical status of the offspring.The rates for any personality disorder (PD) ranged from 7% to 20%. Comorbidity between Axis I and Axis II disorders was high for all groups.

Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation +/- SE) were estimated for sibling (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07 +/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that approximately 40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.