Search

AbstractBackgroundThe aim of this study is to identify differentially methylated regions (DMRs) in the genomes of a sample of cognitively healthy individuals and a sample of individuals with LOAD, all of them nonagenarians from Costa Rica.MethodsIn this study, we compared whole blood DNA methylation profiles of 32 individuals: 21 cognitively healthy and 11 with LOAD, using the Infinium MethylationEPIC BeadChip. First, we calculated the epigenetic age of the participants based on Horvath’s epigenetic clock. DMRcate and Bumphunter were used to identify DMRs. After in silico and knowledge-based filtering of the DMRs, we performed a methylation quantitative loci (mQTL) analysis (rs708727 and rs960603).ResultsOn average, the epigenetic age was 73 years in both groups, which represents a difference of over 20 years between epigenetic and chronological age in both affected and unaffected individuals. Methylation analysis revealed 11 DMRs between groups, which contain six genes and two pseudogenes. These genes are involved in cell cycle regulation, embryogenesis, synthesis of ceramides, and migration of interneurons to the cerebral cortex. One of the six genes is PM20D1, for which altered expression has been reported in LOAD. After genotyping previously reported mQTL SNPs for the gene, we found that average methylation in the PM20D1DMR differs between genotypes for rs708727, but not for rs960603.ConclusionsThis work supports the possible role of PM20D1in protection against AD, by showing differential methylation in blood of affected and unaffected nonagenarians. Our results also support the influence of genetic factors on PM20D1methylation levels.

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2Aand transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Genome‐wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re‐analyze an Irish schizophrenia GWAS dataset (n= 3,473) by performing identity‐by‐descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNTbut did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow‐up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Associations of some risk factors with poor cognition, identified prior to age 75, are reduced or reversed in very old age. The Protected Survivor Model predicts this interaction due to enhanced survival of those with extended risk factor duration. In a younger sample, this study examines the association of cognition with the mean hemoglobin A1c risk factor over the time at risk, according to its duration.

Identifying phenotypes for successful cognitive aging, intact cognition into late-old age (>age 75), can help identify genes and neurobiological systems that may lead to interventions against and prevention of late-life cognitive impairment. The association of C-reactive protein (CRP) with cognitive impairment and dementia, observed primarily in young-elderly samples, appears diminished or reversed in late-old age (75 years). A family history study determined if high CRP levels in late-old aged cognitively intact probands are associated with a reduced risk of dementia in their first-degree family members, suggesting a familial successful cognitive aging phenotype.

As life expectancy in the United States continues to increase, the projected numbers of elderly people who will develop dementia will grow rapidly. This paper reviews four well-established cardiovascular risk factors (type 2 diabetes, hypertension, cholesterol, and inflammation), for which there is longitudinal epidemiological evidence of increased risk of dementia, Alzheimer's disease, mild cognitive impairment, and cognitive decline. These risk factors are of special interest because of their potential modif lability, which may affect the course of cognitive compromise. Diabetes is the cardiovascular risk factor (CvRF) most consistently associated with cognition. Hypertension in midlife is consistently associated with cognition, but its associations with late-life hypertension are less clear. Total cholesterol is not consistently associated with cognition, interleukin-6 and C-reactive protein are inflammatory markers relatively consistently associated with cognition. Composites of the CvRFs increase the risk for dementia in a dose-dependent fashion, suggesting a cumulative effect of these factors on neuronal stress. In the relatively few studies that have reported interactions of risk factors, they potentiate each other. The effect of each of these risk factors varies according to apolipoprotein E genotype, it may be that the effect of these risk factors varies according to the presence of the others, and these complex relationships underlie the biological mechanisms of cognitive compromise. This may be crucial for understanding the effects on cognition of druqs and other approaches, such as lifestyle chanqe, for treatinq these risk factors.

A susceptibility locus for autism was identified to the chromosome 2q24–q33 region in independent cohorts of families, especially in subsets clinically defined with phrase speech delay PSD. In the present work, we screened 84 linkageinformative SNPs covering this locus in a cohort of 334 families with autism and in subsets identified with PSD. We observed linkage to autism with the highest nonparametric linkage score NPL of 2.79 P  0.002 in the PSD subset with at least two affected subjects. In addition, using a set of 109 additional geneoriented SNPs in this interval we observed that several SNPs encompassing the SLC25A12gene provided the maximum evidence for linkage NPL  3.32, P  0.0003. Using the transmission disequilibrium test to test for associations, we observed significant overtransmissions of rs2056202 P  0.006 within the SLC25A12gene, rs1807984 P  0.007 within the STK39gene, and rs2305586 P  0.009 within the ITGA4gene. We also found evidence for association between autism and two other SNPs rs1517342, P  0.012 and rs971257, P  0.030 or haplotypes P  0.003 of the STK39gene. STK39encodes a serinethreonine kinase SPAKPASKSTE20SPS1 homolog abundantly expressed in the brain with roles in cell differentiation, cell transformation and proliferation, and in regulation of ion transporters. In summary, we have observed further evidence for linkage and association between autism and loci within the 2q24–q33 region, including at STK39, a novel candidate gene for autism. © 2008 WileyLiss, Inc.

Life expectancy is a familial trait. However, the effectiveness of using the age at death of a deceased parent to estimate life expectancy in their offspring can vary depending on whether death in the parent was due to extrinsic versus intrinsic causes, as well as demographic characteristics such as sex. While Alzheimers disease AD risk increases with increased age, mortality for individuals with AD is increased in contrast to comparably aged individuals without AD. Yet in most cases it is not the defining neuropathology of AD that directly terminates life but instead conditions and illnesses extrinsic to AD pathology that nevertheless have increased likelihood in its presence. For this reason, we hypothesized that offspring of AD mothers would have greater longevity than offspring of mothers without AD insufficient numbers prevented a comparable analysis using fathers with AD. The longevity of 345 offspring of 100 deceased 60 year old AD mothers was compared with 5,465 offspring in 1,312 deceased 60 year old nonAD mothers. We used a proportional hazards model that accounted for clustered nonindependent observations due to the inclusion of several offspring from the same family. In both an unadjusted model and one that adjusted for the age at death in the mother, and the sex and birth year in the offspring we found evidence for increased longevity in the offspring of AD mothers. The results suggest that, in addition to genes that might directly affect pathways leading to AD, there may be familialgenetic factors not connected to specific pathophysiological processes in AD but instead associated with increased longevity that contribute to the familial aggregation observed in AD. © 2007 WileyLiss, Inc.

Survival from Alzheimer's disease (AD) and other dementias into late old age may be a useful phenotype for genetic studies of successful cognitive aging. To support molecular genetics studies for successful cognitive aging, we conducted a two‐stage study to determine an optimal age phenotype for successful cognitive aging. First, risk of AD was evaluated, through informant interviews, in 4,794 parents and siblings of 976 elderly nondemented probands who were divided into three different proband age groups: those aged 60–74, 75–89, and 90+. Relatives of probands aged 90+ had a significantly lower risk than the relatives of the other two proband groups. Second, this sample was combined with an earlier sample (combined nondemented elderly probands: n = 2,025; relatives: n = 10,506), and a series of proband age groups (i.e., 75–79, 80–84, 85–89, 90+) were used to determine which optimally identifies a group of relatives with low AD risk. Using the relatives of the nondemented proband aged 60–74 as the reference group, there were reductions in cumulative risk among relatives of probands aged 85–89 and 90+, but only the latter group also showed significant reductions to the relatives of probands aged 75–79, 80–84, and 85–89. This pattern of results varied little by sex. Finally, cumulative AD risk curves were similar between relatives of probands aged 90–94 and 95+. These results suggest that age 90 is an optimal age threshold to use for both men and women in genetic studies seeking to identify genes associated with successful cognitive aging. © 2007 Wiley‐Liss, Inc.

Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Lhermitte–Duclos disease. In addition, PTEN mutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as ≥2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation‐dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5‐year‐old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte–Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN‐related tumor syndromes. © 2007 Wiley‐Liss, Inc.

An autism susceptibility locus (AUTS1, MIM608636) has been identified in chromosome 7q31. NrCAM is a candidate gene for AUTS1 because it is expressed in the brain and encodes a receptor involved in nervous system development. Polymorphisms in NrCAM have been reported to be associated with autism susceptibility and with substance abuse, implicating NrCAM in reward circuitry. Self-stimulatory, perseverative behavior in autism might be due to defects in reward circuitry. In addition, models of drug addiction have also borrowed from models of obsessive–compulsive behavior designed to reduce anxiety. Thus, our goals were to replicate previous associations of NrCAM with autism, making use of a large cohort, and to clarify whether NrCAM was associated with a specific endophenotype of autism in the repetitive behaviors and stereotyped interests domains.

The TPH1 and TPH2 genes encode the rate‐limiting enzymes that control serotonin biosynthesis, and serotonin is clearly altered in autism. In the current study, eight SNPs in the TPH1 gene region and eight SNPs within the TPH2 gene were examined by family‐based association tests in a large cohort of 352 families with autism and in clinically defined subsets of these families with either severe obsessive‐compulsive behaviors (sOCB) or self‐stimulatory behaviors (SSB). We found no evidence for association between autism and single SNPs or haplotypes of the TPH1 and TPH2 genes in the cohort of all families or in the sOCB and SSB subsets. In particular, we failed to replicate the association between autism and variants of the TPH2 gene, rs4341581 (TRANSMIT P = 1; PDT P = 0.323; FBAT P = 0.446) and rs11179000 (TRANSMIT P = 0.174; PDT P = 0.293; FBAT P = 0.374). Furthermore, no evidence for linkage was observed between autism and SNPs in the TPH1 and TPH2 genes (although linkage at the TPH2 locus was observed in the SSB subset). Thus, it appears unlikely that the TPH1 and TPH2 genes play a significant role in the susceptibility to autism or to autism endophenotypes including sOCB and SSB. © 2006 Wiley‐Liss, Inc.

A locus involved in schizophrenia and related disorders in a Puerto Rican family has previously been mapped to chromosome 5p. The maximum two-point log of the odds (LOD) score of 3.72 was obtained for marker D5S111, and increased to 4.37 by multipoint analysis, assuming autosomal dominant inheritance with 90 penetrance. Additional genotyping and haplotype analysis placed the novel locus on 5p13.2–p13.3 within the interval between markers D5S1993 and D5S631. In the current study, we saturated the interval between markers D5S1993 and D5S631 with densely spaced polymorphic markers, genotyped these markers in the most informative branch of the family, and narrowed the critical region to 2.8 Mb. G-protein-coupled receptor gene somatostatin and angiotensin-like peptide receptor (SALPR) is one of the candidate genes within the critical interval. Sequence analysis of the coding region and the putative promoter of somatostatin and angiotensin-like peptide receptor did not reveal functionally significant variants in affected family members, although several polymorphisms were detected.

Autism is characterized by a triad of symptom domains (impaired social interaction, communication deficits, and repetitive behaviors) that vary significantly in their clinical presentation across the population. Within families with more than one affected member, however, discrepant findings exist with regard to symptom variability. Reduced intrafamily variance is of particular importance because it supports an underlying model of genetic heterogeneity in the transmission of autism, and the identification of familial clinical subtypes can be used to select more homogeneous samples for linkage analysis in the future. This study examines whether there are specific features of autism that show decreased variance within 16 families with monozygotic siblings concordant for autism. Evidence for familiality was defined as significantly decreased variance of symptom levels within monozygotic siblingships as compared to between siblingships. Using regression analysis, we demonstrated significant aggregation of symptoms within monozygotic siblingships for two of the three main symptom domains in autism: impairments in communication and social interaction showed significant familiality. Within the repetitive behavior domain, only the categories of circumscribed interests and preoccupation with part‐objects showed reduced variance within siblingships. In addition, with the exception of a negative association between the social and behavior domains, partial correlation coefficients did not reveal significant associations between the levels of different symptom domains within families, suggesting that the levels of clinical features seen in autism may be a result of mainly independent genetic traits. Because of presumed genetic heterogeneity and the wide clinical variation seen in autism and other pervasive developmental disorders, selecting probands according to specific features known to show reduced variance within families may provide more homogeneous samples for genetic analysis and strengthen the power to detect the specific genes involved in autism. © 2004 Wiley‐Liss, Inc.

ABSTRACTBackground:This study examined the relationship of self-reported histories of childhood trauma to measures of affective instability in a sample of unmedicated outpatients with various personality disorders (n=174).Methods:Childhood trauma was measured by the Childhood Trauma Questionnaire. Affective instability comprises at least two dimensions: affective lability, assessed using the Affective Lability Scale, and affective intensity, assessed using the Affective Intensity Measure.Results:A history of emotional abuse was the only trauma variable that significantly correlated with the affect measures in the total sample(r=.21–.30). More fine-grained analyses revealed that the relationship of emotional abuse and affective instability measures varied as a function of both gender and personality disorder type. In subjects with borderline personality disorder, the correlation for emotional abuse was greatly attenuated for both Affective Lability Scale(r=.10) and Affective Intensity Measure(r=.15) total scores.Conclusion:This suggests that nontrauma-related factors may be more predominant in affective dyscontrol in individuals with borderline personality disorder.

ABSTRACTBackground:Childhood history of abuse and neglect has been associated with personality disorders and has been observed in subjects with lifetime histories of suicidality and self-injury. Most of these findings have been generated from inpatient clinical samples.Methods:This study evaluated self-rated indices of sustained childhood abuse and neglect in an outpatient sample of well-characterized personality disorder subjects (n=182) to determine the relative associations of childhood trauma indices to specific personality disorder diagnoses or clusters and to lifetime history of suicide attempts or gestures. Subjects met criteria for ~2.5 Axis II diagnoses and 24% reported past suicide attempts. The Childhood Trauma Questionnaire was administered to assess five dimensions of childhood trauma exposure (emotional, physical, and sexual abuse, and emotional and physical neglect). Logistic regression was employed to evaluate salient predictors among the trauma measures for each cluster, personality disorder, and history of attempted suicide and self-harm. All analyses controlled for gender distribution.Results:Seventy-eight percent of subjects met dichotomous criteria for some form of childhood trauma; a majority reported emotional abuse and neglect. The dichotomized criterion for global trauma severity was predictive of cluster B, borderline, and antisocial personality disorder diagnoses. Trauma scores were positively associated with cluster A, negatively with cluster C, but were not significantly associated with cluster B diagnoses. Among the specific diagnoses comprising cluster A, paranoid disorder alone was predicted by sexual, physical, and emotional abuse. Within cluster B, only antisocial personality disorder showed significant associations with trauma scores, with specific prediction by sexual and physical abuse. For borderline personality disorder, there were gender interactions for individual predictors, with emotional abuse being the only significant trauma predictor, and only in men. History of suicide gestures was associated with emotional abuse in the entire sample and in women only; self-mutilatory behavior was associated with emotional abuse in men.Conclusion:These results suggest that childhood emotional abuse and neglect are broadly represented among personality disorders, and associated with indices of clinical severity among patients with borderline personality disorder. Childhood sexual and physical abuse are highlighted as predictors of both paranoid and antisocial personality disorders. These results help qualify prior observations of the association of childhood sexual abuse with borderline personality disorder.

ABSTRACTBackground:Personality traits have been hypothesized to involve specific neurotransmitter systems. In order to test this model, the relationship between the responses to serotonergic and noradrenergic probes, central cerebrospinal fluid (CSF) measures of monoamine neurotransmitters and the Tridimensional Personality Questionnaire (TPQ) were evaluated in a cohort of personality disorder subjects.Methods:A total of 142 patients meeting at least one personality disorder(meetingDiagnostic and Statistical Manual of Mental Disorders, Third Edition–Revised criteria) participated in these studies. The prolactin response to fenfluramine(a measure of serotonin function) was obtained for 110 subjects; growth hormone response to clonidine(a measure of noradrenergic function) was obtained for 77 subjects, while homovanillic acid (HVA) at baseline, an index of dopaminergic function, was available for 103 subjects. Measures of central neurotransmitter function (dopaminergic, serotonergic, and noradrenergic: HVA, 5-hydroxyindolacetic acid, and 3-methoxy-4-hydroxyphenylglycol, respectively) were available for 36 subjects. Separate regression analyses utilizing each of the hypothesized associations, where the TPQ total scores were used as the dependent measures and the biologic indices were the independent measures were conducted. Exploratory correlational analyses between these biologic measures and the four dimensions of the TPQ (and its subscales) were also conducted. (Correlations are reported if they would remain significant atP<.01 level after Bonferroni correction for multiple comparisons across the six neuroendocrine measures).Results:In the regression analyses, there was a trend association between CSF and plasma HVA in predicting novelty-seeking(P<.07). No other significant associations were found in the other three measures. Regarding the individual correlational analyses, the persistence scale of the TPQ was significantly positively correlated with the growth hormone response to clonidine(r=.30, P<.008). The sentimentality subscale (reward dependence) was positively correlated with CSF 5-hydroxyindolacetic acid(r=0.45, P<.001), while the attachment subscale (also reward dependence) was correlated with CSF 3-methoxy-4-hydroxyphenylglycol(r=0.49, P<.002).Conclusion:Limited support was provided for a relationship between monoamines, particularly dopamine and novelty-seeking as well as norepinephrine and reward dependence but other hypothesized relationships were not supported by these measures.

Heterogeneity in autism impairs efforts to localize and identify the genes underlying this disorder. As autism comprises severe but variable deficits and traits in three symptom domains (social interaction, communication, and repetitive behaviors) and shows variability in the presence and emergence of useful phrase speech, different genetic factors may be associated with each. The affected cases (n = 457) in multiply affected siblingships (n = 212), including a proband with autism and one or more siblings with either autism or marked deficits in autism symptom domains, were assessed using the Autism Diagnostic Interview, Revised. Symptom domain scores and language features were examined to determine their similarity within siblingships. The variance within siblingships was reduced for the repetitive behavior domain and for delays in and the presence of useful phrase speech. These features and the nonverbal communication subdomain provided evidence of familiality when we considered only the diagnosis of autism to define multiply affected siblingships (cases: n = 289; siblingships: n = 136). In addition, the same familial features identified also appeared familial for those with autism-related conditions. Finally, the level of severity of almost all of the familial features varied within multiplex siblingships independently. The features identified as familial replicate the combined set suggested in earlier, smaller studies. Furthermore, the familiality of these features extend to related conditions of milder severity than autism and appear to be independent. Making distinctions among families by the severity of these features may be useful for identifying more genetically homogeneous subgroups in studies targeted at genes for specific autism-related symptom domains. © 2001 Wiley-Liss, Inc.

We systematically and comprehensively investigated polymorphisms of the HTR1Bgene as well as their linkage disequilibrium and ancestral relationships. We have detected the following polymorphisms in our sample via denaturing gradient gel electrophoresis, database comparisons, and/or previously published assays: G-511T, T-261G, –182INS/DEL-181, A-161T, C129T, T371G, T655C, C705T, G861C, A1099G, G1120A, and A1180G. The results of the intermarker analyses showed strong linkage disequilibrium between the C129T and the G861C polymorphisms and revealed four common haplotypes: ancestral (via chimpanzee comparisons), 129T/861C, -161T, and -182DEL-181. The results of association tests with schizophrenia were negative, although A-161T had a nominal P= 0.04 via ASPEX/sib_tdt. The expressed missense substitutions, Phe124Cys, Phe219Leu, Ile367Val, and Glu374Lys, could potentially affect ligand binding or interaction with G proteins and thus modify drug response in carriers of these variants. On average, the human cSNPs and differences among other primates clustered in the more thermodynamically unstable regions of the mRNA, which suggests that the evolutionary survival of nucleotide sequence variation may be influenced by the mRNA structure of this gene.

In a previous genome scan of 43 schizophrenia pedigrees, nonparametric linkage (NPL) scores with empirically derived pointwise P-values less than 0.01 were observed in two regions (chromosomes 2q12-13 and 10q23) and less than 0.05 in three regions (4q22-23, 9q22, and 11q21). Markers with a mean spacing of about 5 cM were typed in these regions in an expanded sample of 71 pedigrees, and NPL analyses carried out. No region produced significant genomewide evidence for linkage. On chromosome 10q, the empirical P-value remained at less than 0.01 for the entire sample (D10S168), evidence in the original 43 pedigrees was slightly increased, and a broad peak of positive results was observed. P-values less than 0.05 were observed on chromosomes 2q (D2S436) and 4q (D4S2623), but not on chromosomes 9q or 11q. It is concluded that this sample is most supportive of linkage on chromosome 10q, with less consistent support on chromosomes 2q and 4q. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:864–869, 2000. © 2000 Wiley-Liss, Inc.

No abstract.

Recent evidence for mitochondrial mutations associated with Alzheimers disease (AD) suggests the possibility of maternal transmission of this illness. We investigated this hypothesis by examining, in a variety of ways, the risk of a primary progressive dementia (PPD) in the parents (n = 650) and siblings (n = 1,220) of 325 AD probands. The results did not support maternal transmission in AD: The mothers of AD probands were not at greater risk of PPD than the fathers or the sisters of AD probands; the offspring of affected mothers were not at greater risk than the offspring of affected fathers or families with no affected parent; and, after selecting those proband families with evidence for increased familial loading, such families did not more frequently have affected mothers than fathers. In contrast, the cumulative risk of PPD in fathers of AD probands, while similar to that of mothers, was significantly increased over the brothers of AD probands. In addition, the cumulative risk curve of PPD in the offspring of affected fathers was significantly higher than the offspring of no affected parents. While no evidence for maternal transmission in AD was observed, unexpectedly, we did find evidence of increased paternal transmission. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:378–382, 1999. © 1999 Wiley-Liss, Inc.

Evidence for suggestive linkage to schizophrenia with chromosome 6q markers was previously reported from a two-stage approach. Using nonparametric affected sib pairs (ASP) methods, nominal p-values of 0.00018 and 0.00095 were obtained in the screening (81 ASPs; 63 independent) and the replication (109 ASPs; 87 independent) data sets, respectively. Here, we report a follow-up study of this 50cM 6q region using 12 microsatellite markers to test for linkage to schizophrenia. We increased the replication sample size by adding an independent sample of 43 multiplex pedigrees (66 ASPs; 54 independent). Pairwise and multipoint nonparametric linkage analyses conducted in this third data set showed evidence consistent with excess sharing in this 6q region, though the statistical level is weaker (p=0.013). When combining both replication data sets (total of 141 independent ASPs), an overall nominal p-value=0.000014 (LOD=3.82) was obtained. The sibling recurrence risk (λs) attributed to this putative 6q susceptibility locus is estimated to be 1.92. The linkage region could not be narrowed down since LOD score values greater than three were observed within a 13cM region. The length of this region was only slightly reduced (12cM) when using the total sample of independent ASPs (204) obtained from all three data sets. This suggests that very large sample sizes may be needed to narrow down this region by ASP linkage methods. Study of the etiological candidate genes in this region is ongoing. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:337–343, 1999. © 1999 Wiley-Liss, Inc.

OBJECTIVE: To examine the validity of the family history method for identifying Alzheimer disease (AD) by comparing family history and neuropathological diagnoses. METHODS: Seventy-seven former residents of the Jewish Home and Hospital for the Aged, New York, NY, with neuropathological evaluations on record were blindly assessed for the presence of dementia and, if present, the type of dementia through family informants by telephone interviews. The Alzheimer's Disease Risk Questionnaire was used to collect demographic information and screen for possible dementia. If dementia was suspected, the Dementia Questionnaire was administered to assess the course and type of dementia, ie, primary progressive dementia (PPD, likely AD), multiple infarct dementia, mixed dementia (ie, PPD and multiple infarct dementia), and other dementias based on the modified Diagnostic and Statistical Manual of Mental Disorders, Third Edition, criteria. RESULTS: Sixty (77.9%) of 77 elderly subjects were classified as having dementia and 17 (22.1%) were without dementia by family history evaluation. Of the 60 elderly subjects with dementia, 57 (95%) were found at autopsy to have had neuropathological changes related to dementia. The sensitivity of the family history diagnosis for dementia with related neuropathological change was 0.84 (57 of 68) and the specificity was 0.67 (6 of 9). Using family history information to differentiate the type of dementia, the sensitivity for definite or probable AD (with or without another condition) was 0.69 (36 of 51) and the specificity was 0.73 (19 of 26). The majority (9 of 15) of patients testing false negative for PPD had a history of stroke associated with onset of memory changes, excluding a diagnosis of PPD. CONCLUSIONS: Identifying dementia, in general, and AD, in particular, has an acceptable sensitivity and specificity. As is true for direct clinical diagnosis, the major issue associated with misclassifying AD in a family history assessment is the masking effects of a coexisting non—AD dementia or dementia-related disorders, such as stroke. Including mixed cases, ie, PPD and multiple infarct dementia in estimates of the familial risk for AD can reduce the extent of underestimation of PPD.

BACKGROUND: Biological relatives of patients with schizophrenia demonstrate an increased prevalence of schizotypal personality disorder symptoms, eye tracking deficits, and attentional disturbances. We investigated whether these hypothesized components of a schizophrenia-related phenotype are associated with one another or are independent in nonpsychotic relatives of patients with schizophrenia. METHODS: Eighty-three nonpsychotic first-degree relatives of 38 patients with schizophrenia and 45 control subjects without a psychiatric diagnosis underwent clinical evaluation, eye tracking evaluation, and the Continuous Performance Test (CPT) of visual attention. RESULTS: Eye tracking qualitative rating was more powerful than quantitative eye tracking measures or CPT measures in discriminating relatives of patients with schizophrenia from control subjects. Correlations between neurocognitive variables and DSM-III-R schizotypal personality disorder symptom clusters suggested that CPT errors of omission are associated with positive schizotypal symptoms. Eye tracking measures were not significantly correlated with schizotypal symptoms or CPT errors in relatives of patients with schizophrenia. CONCLUSIONS: Eye tracking deficits in the relatives of patients with schizophrenia are unrelated to CPT deficits and schizotypal symptoms. Eye tracking deficits and disturbances in visual attention may be separate components of a schizophrenia-related phenotype and should be considered as independent factors in genetic studies of schizophrenia.

• To evaluate whether probands from a clinical sample diagnosed as having DSM-III schizotypal and/or paranoid personality disorder have a familial relationship to the schizophrenia-related disorders, the morbid risk for schizophrenia-related disorders and other psychiatric disorders were evaluated in the first-degree relatives of patients with schizotypal and/or paranoid personality disorder and compared with the corresponding risk for these disorders in the first-degree relatives of patients with other non-schizophrenia-related personality disorders. The morbid risk for all schizophrenia-related disorders, and specifically for schizophrenia-related personality disorders, was significantly greater among the relatives of the probands with schizotypal and/or paranoid personality disorder than among the relatives of probands with other personality disorder. The morbid risk for other psychiatric disorders did not differ significantly between the first-degree relatives of the schizotypal/paranoid personality disorder and the other personality disorder control proband samples. These results suggest a specific familial association between schizophrenia-related disorders, particularly schizophrenia-related personality disorders, and clinically diagnosed schizotypal patients.

Although the morbid risk of Alzheimer's disease (AD) is increased among relatives of AD index cases, it is not yet clear whether the extent of familial aggregation is similar for probands of all ages, or for male and female relatives. The present study investigated the incidence of AD-like illness among 379 first-degree relatives of 79 probands in a continuing longitudinal study of AD. Cumulative incidence among relatives increased strikingly with age to 49 by age 87, and the risks observed did not differ appreciably among relatives of presenile-onset versus senile-onset probands. Risks were also similar among parents and sibs. Female relatives appeared to develop the disease earlier than males, but the age-specific risk curves for the two sexes did not differ significantly. These results should not be viewed as direct evidence for dominant genetic transmission of late-onset AD, but they suggest a rationale for formal genetic studies in late-onset (often apparently “sporadic”) disease as well as earlier-onset (“familial”) cases.

BACKGROUND: Although an increased cumulative risk for primary progressive dementia (PPD) has been repeatedly demonstrated in relatives of probands with Alzheimer's disease (AD), an examination of their rates of illness at different ages has not been previously undertaken. Such an examination might reveal possible age-related characteristics associated with a more familial variety of AD. METHODS: Using family history interviews and survival analysis, the cumulative risk for and 5-year age-specific hazard rates of PPD were assessed in the first-degree relatives of 200 probands with AD and two nondemented control groups—179 elderly ascertained through the Alzheimer's Disease Research Center (ADRC-derived controls) and 427 elderly ascertained from community senior centers (community controls). RESULTS: The PPD risk curve for the relatives of probands with AD rose to about 30% and was significantly higher than the curves for the relatives of the ADRCderived and community controls, where comparable rates were observed (approximately 12%). The age-specific hazard rates of PPD were calculated in three groups of relatives for each 5-year interval from ages 45 to 49 years through ages 85 to 89 years. The age-specific relative risk (RR,) for PPD in the relatives of probands with AD began to steadily diminish from the 75- to 79-year age interval (RRi=13.49) through the 85- to 89-year age interval (RRi=0.96) compared with the relatives of ADRCderived controls and from the 60- to 64-year age interval (RRi=16.15) through the 85- to 89-year age interval (RRi=2.03) compared with the relatives of the community controls. CONCLUSIONS: These data indicate that, for relatives of probands with AD, while the lifetime risk for PPD is greater than in relatives of controls, the familial contribution to the risk for PPD decreases with increasing age. The higher risk for PPD in relatives of probands with AD may be substantially diminished or even eliminated by the latter half of the ninth decade.

BACKGROUND: To test the hypothesis that evidence of reduced central serotonergic (5-HT) system function in probands with personality disorders is associated with an elevated morbid risk of psychopathological conditions putatively associated with 5-HT dysfunction in firstdegree relatives of these probands.Methods:Data were collected during a study of the 5-HT correlates of behavior in male patients with DSM-III personality disorders conducted at a Veterans Affairs medical center. Probands in this study were selected from those patients who had undergone both a fenfluramine hydrochloride challenge and a family history assessment. Axis II diagnoses were made acording to DSM-III criteria after a structured interview of the proband, using the Structured Interview for Diagnosing Personality Disorders, given by two raters and a similar interview with a knowledgeable informant by another rater. RESULTS: Reduced prolactin responses to the 5-HT releasing/uptake inhibiting agent fenfluramine was associated with an elevated morbid risk of impulsive personality disorder traits in the first-degree relatives of patients with a primary DSM-III diagnosis of a personality disorder. Quantitative scores on assessments of impulsive aggression in the probands were not correlated with an increased morbid risk for impulsive personality disorder traits. A trend in the same direction was noted for affective personality disorder traits and alcoholism. CONCLUSIONS: These results suggest that a central 5-HT system abnormality in probands is associated with an increased risk of impulsive aggression in their first-degree relatives, and that assessment of central 5-HT system function in probands may be a more sensitive parameter for identification of this familial trait than the presence of impulsive aggressive behaviors in the proband.

• The morbid risk of Alzheimer's disease was studied in first-degree relatives of 50 patients who met contemporary clinical research diagnostic criteria and 45 matched controls. Relatives of patients showed a 46% cumulative incidence of probable Alzheimer's disease by 86 years of age. The risk, which was four times the control value, is consistent with other recent reports using similar, modern methods. Although not conclusive, the data suggest the operation of a relatively common, dominant autosomal gene for Alzheimer's disease, the expression of which is delayed until late old age but is largely complete by 90 years of age.

Evidence for a genetic association between autism and two single nucleotide polymorphisms (SNPs), rs2056202 and rs2292813, in the mitochondrial aspartate/glutamate carrier (SLC25A12) gene led us to ask whether any of the four previously identified familial traits in autism spectrum disorders (ASD) varied by these SNPs. In 355 ASD cases from 170 sibships we examined levels of the four traits in these SNPs using ANCOVA models. The primary models selected unrelated affected cases and used age and sex as covariates. An ancillary set of models used all affected siblings and included “sibship” as a random effects independent variable. We found significantly lower levels of routines and rituals associated with the presence of the less frequent A allele in rs2056206. No other significant differences were observed. The rs2056202 polymorphism may be associated with levels of routines and rituals in autism and related disorders. © 2007 Wiley‐Liss, Inc.