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Background: Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are typically associated with very different clinical and neuroanatomical presentations; however, there is increasing recognition of similarities.Objective: To examine memory and executive functions, as well as cortical thickness, and glucose metabolism in AD and bvFTD signature brain regions.Methods: We compared differences in a group of biomarker-defined participants with Alzheimer’s disease and a group of clinically diagnosed participants with bvFTD. These groups were also contrasted with healthy controls (HC).Results: As expected, memory functions were generally more impaired in AD, followed by bvFTD, and both clinical groups performed more poorly than the HC group. Executive function measures were similar in AD compared to bvFTD for motor sequencing and go/no-go, but bvFTD had more difficulty with a set shifting task. Participants with AD showed thinner cortex and lower glucose metabolism in the angular gyrus compared to bvFTD. Participants with bvFTD had thinner cortex in the insula and temporal pole relative to AD and healthy controls, but otherwise the two clinical groups were similar for other frontal and temporal signature regions.Conclusions: Overall, the results of this study highlight more similarities than differences between AD and bvFTD in terms of cognitive functions, cortical thickness, and glucose metabolism. Further research is needed to better understand the mechanisms mediating this overlap and how these relationships evolve longitudinally.

Introduction:Genome-wide association studies (GWAS) have played a critical role in identifying many thousands of loci associated with complex phenotypes and diseases. This has led to several translations of novel disease susceptibility genes into drug targets and care. This however has not been the case for analyses where sample sizes are small, which suffer from multiple comparisons testing. The present study examined the statistical impact of combining a burden test methodology, PrediXcan, with a multimodel meta-analysis, cross phenotype association (CPASSOC). Methods:The analysis was conducted on 5 addiction traits: family alcoholism, cannabis craving, alcohol, nicotine, and cannabis dependence and 10 brain tissues: anterior cingulate cortex BA24, cerebellar hemisphere, cortex, hippocampus, nucleus accumbens basal ganglia, caudate basal ganglia, cerebellum, frontal cortex BA9, hypothalamus, and putamen basal ganglia. Our sample consisted of 1,640 participants from the University of California, San Francisco (UCSF) Family Alcoholism Study. Genotypes were obtained through low pass whole genome sequencing and the use of Thunder, a linkage disequilibrium variant caller. Results:The post-PrediXcan, gene-phenotype association without aggregation resulted in 2 significant results, HCG27and SPPL2B. Aggregating across phenotypes resulted no significant findings. Aggregating across tissues resulted in 15 significant and 5 suggestive associations: PPIE, RPL36AL, FOXN2, MTERF4, SEPTIN2, CIAO3, RPL36AL, ZNF304, CCDC66, SSPOP, SLC7A9, LY75, MTRF1L, COA5,and RRP7A; RPS23, GNMT, ERV3-1, APIP, and HLA-B,respectively. Discussion:Given the relatively small size of the cohort, this multimodel approach was able to find over a dozen significant associations between predicted gene expression and addiction traits. Of our findings, 8 had prior associations with similar phenotypes through investigation of the GWAS Atlas. With the onset of improved transcriptome data, this approach should increase in efficacy.

This case report investigates the potential use of metabolism as a sensitive biomarker in monitoring the effectiveness of anti-amyloid therapy in a patient with mild cognitive impairment due to early Alzheimer's disease. The study centers around a 74-year-old male patient treated with aducanumab, a monoclonal antibody developed for anti-amyloid therapy. Alongside an expected decline in cerebral amyloid monitored using PET amyloid tracers, we observed significant improvements in the patient's brain metabolic activity, measured via 18-fluorodeoxyglucose positron emission tomography (FDG PET). Despite limitations posed by the single-patient case study, the findings invite further research and consider the utilization of FDG PET as a surrogate for clinically meaningful changes in the treatment of early Alzheimer's disease. These findings suggest the potential for more personalized and effective therapeutic interventions.

Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1,and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P= 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

•Screening for amnestic disorder must differentiate changes associated with normal aging.•Using an odorant identification test, the authors identified specific odorants which best differentiate amnestic disorder from normal aging. The identified odorants were validated with performance on neuropsychological testing and prediction of conversion from amnestic mild cognitive impairment to Alzheimer disease.•Olfactory identification impairment was associated with poor performance in numerous cognitive domains and was predictive of progression of mild cognitive impairment.•Olfactory identification deficit can be utilized for risk stratification of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and to enrich clinical trials of potential disease-modifying therapies for converters.

Higher rates of alcohol use disorders (AUD) have been observed in some Native American populations than other ethnic groups such as European Americans (EAs) in the United States. Previous studies have shown that variation in the alcohol dehydrogenase (ADH) genes may affect the risk for development of AUDand that the prevalence of these variants differs depending on the ancestral origins of a population. In this study, we assessed sequencing variants in the ADHgenomic region (ADH1‐7) and tested for their associations with AUDphenotypes in 2 independent populations: an American Indian (AI) community sample and an EAcohort from the San Francisco Family Alcohol Study. Association tests were conducted for both common and rare variants using sequencing data for 2 phenotypes: the number of alcohol‐related life events and the count of alcohol dependence drinking symptoms. A regularized regression method was used to select the best set of ADHvariants associated with phenotypes. Variance component model was incorporated in all analyses to leverage the admixture and relatedness. Two variants near ADH4and 2 near ADH1Cexhibited significant associations with AUDin AIs; no variant was significant in EAs. Common risk variants in AIs were either absent from or much less frequent in EAs. The feature selection method selected mostly distinct yet often colocated subsets of ADHvariants to be associated with AUDphenotypes between the 2 cohorts. In the rare‐variant analyses, the only association was observed between the whole region and the alcohol‐related life events in AIs. Our results suggest that ADHvariants, both common and rare, are more likely to impact risk for alcohol‐related symptomatology in this AIpopulation than in this EAsample, and ADHvariants that might affect AUDare likely different but convergent on similar regions between the 2 populations. Elevated alcohol use disorder rates have been observed in some American Indians (AI) relative to other U.S. ethnic groups such as Euro‐Americans (EA). A comparison of an AI versus an EA sample of sequencing variants in the ADH1‐7genomic region showed that both common & rare ADHvariants might confer increased likelihood of risk impaction in AI for alcohol‐related symptomatology. The potential risk ADHvariants are mostly different although often convergent onto the same genomic regions across both populations.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Nicotine dependence (ND) has a reported heritability of 40–70%. Low‐coverage whole‐genome sequencing was conducted in 1,889 samples from the UCSF Family study. Linear mixed models were used to conduct genome‐wide association (GWA) tests of ND in this and five cohorts obtained from the database of Genotypes and Phenotypes. Fixed‐effect meta‐analysis was carried out separately for European (n= 14,713) and African (n= 3,369) participants, and then in a combined analysis of both ancestral groups. The meta‐analysis of African participants identified a significant and novel susceptibility signal (rs56247223; p= 4.11 × 10−8). Data from the Genotype‐Tissue Expression (GTEx) study suggested the protective allele is associated with reduced mRNA expression of CACNA2D3in three human brain tissues (p< 4.94 × 10−2). Sequence data from the UCSF Family study suggested that a rare nonsynonymous variant in this gene conferred increased risk for ND (p= 0.01) providing further support for CACNA2D3involvement in ND. Suggestive associations were observed in six additional regions in both European and merged populations (p< 5.00 × 10−6). The top variants were found to regulate mRNA expression levels of genes in human brains using GTEx data (p< 0.05): HAX1and CHRNB2(rs1760803), ADAMTSL1(rs17198023), PEX2(rs12680810), GLIS3(rs12348139), non‐coding RNA for LINC00476(rs10759883), and GABBR1(rs56020557 and rs62392942). A gene‐based association test further supported the relation between GABBR1and ND (p= 6.36 × 10−7). These findings will inform the biological mechanisms and development of therapeutic targets for ND.

EEG alpha activity is the dominant oscillation in most adult humans, is highly heritable, and has been associated with a number of cognitive functions. Two EEG phenotypes, low‐ and high‐voltage alpha (LVA & HVA), have been demonstrated to have high heritabilities. They have different prevalence depending on a population's ancestral origins. In the present study we assessed the influence of ancestry admixture on EEG alpha power, and conducted a whole genome sequencing association analysis and an ancestry‐informed polygenic study on those phenotypes in a Native American (NA) population that has a high prevalence of LVA. Seven common variants, in LD with each other upstream from gene ASIC2, reached genome‐wide significance (p= 2 × 10−8) having a positive association with alpha voltage. They had lower minor allele frequencies in the NAs than in a global population sample. Overall correlations between lower degrees of NA (higher degree European) ancestry and HVA, and higher degrees of NA and LVA were also found. Additionally a rare‐variant gene‐based study identified gene TIA1being negatively associated with LVA. Approximately 3% of SNPs exhibited a 15‐fold enrichment that explained nearly half of the total SNP‐heritability for EEG alpha. These regions showed the most significant anti‐correlations between NA ancestry and alpha voltage, and were enriched for genes and pathways mediating cognitive functions. Our findings suggested that these regions likely harbor causal variants for HVA, and lacking of such variants could explain the high prevalence of LVA in this NA population, possibly illuminating the ancestral origin and genetic basis for EEG alpha.

BackgroundIncreased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.Methods and resultsWe conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE(β=56.3, pinteraction=3.9e−9) and rs9830388 in UBE2E2(β=25.2, pinteraction=1.7e−8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e−8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.ConclusionsAmong Europeans, TCA interactions with variants in BREand UBE2E2were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

Purpose:As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis.Methods:We established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15.Results:The semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test).Conclusion:Gene–disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts.Genet Med 18 5, 467–475.

As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis.

Purpose:Next-generation sequencing has transformed genetic research and is poised to revolutionize clinical diagnosis. However, the vast amount of data and inevitable discovery of incidental findings require novel analytic approaches. We therefore implemented for the first time a strategy that utilizes an a priori structured framework and a conservative threshold for selecting clinically relevant incidental findings.Methods:We categorized 2,016 genes linked with Mendelian diseases into “bins” based on clinical utility and validity, and used a computational algorithm to analyze 80 whole-genome sequences in order to explore the use of such an approach in a simulated real-world setting.Results:The algorithm effectively reduced the number of variants requiring human review and identified incidental variants with likely clinical relevance. Incorporation of the Human Gene Mutation Database improved the yield for missense mutations but also revealed that a substantial proportion of purported disease-causing mutations were misleading.Conclusion:This approach is adaptable to any clinically relevant bin structure, scalable to the demands of a clinical laboratory workflow, and flexible with respect to advances in genomics. We anticipate that application of this strategy will facilitate pretest informed consent, laboratory analysis, and posttest return of results in a clinical context.Genet Med 2013:15(1):36–44

Epidemiological and clinical studies suggest that the rates of antisocial behavior, depression, and impulsive substance use are increased among individuals diagnosed with alcohol dependence relative to those who are not. Thus, the present study conducted genome-wide linkage scans of antisocial behavior, depression, and impulsive substance use in the University of California at San Francisco Family Alcoholism Study.

Background: Previous linkage studies, including a study of the Native American population described in the present report, have provided evidence for linkage of alcohol dependence and related traits to chromosome 4q near a cluster of alcohol dehydrogenase (ADH) genes, which encode enzymes of alcohol metabolism.

This study's aims were to map loci linked to self-rating of the effects of alcohol and to determine if there was overlap with loci mapped earlier for other substance dependence phenotypes in an American Indian community at high risk for substance dependence.

Cannabis is the most widely used illicit drug in the United States. There is ample evidence that cannabis use has a heritable component, yet the genes underlying cannabis use disorders are yet to be completely identified. This studys aims were to map susceptibility loci for cannabis use and dependence and two narrower cannabisrelated phenotypes of “craving” and “withdrawal” using a family study design. Participants were 2,524 adults participating in the University of California San Francisco UCSF Family Alcoholism Study. DSMIV diagnoses of cannabis dependence, as well as indices of cannabis craving and withdrawal, were obtained using a modified version of the SemiStructured Assessment for the Genetics of Alcoholism SSAGA. Genotypes were determined for a panel of 791 microsatellite polymorphisms. Multipoint variance component LOD scores were obtained using SOLAR. Genomewide significance for linkage LOD > 3.0 was not found for the DSMIV cannabis dependence diagnosis; however, linkage analyses of cannabis “craving” and the cannabis withdrawal symptom of “nervous, tense, restless, or irritable” revealed five sites with LOD scores over 3.0 on chromosomes 1, 3, 6, 7, and 9. These results identify new regions of the genome associated with cannabis use phenotypes as well as corroborate the importance of several chromosome regions highlighted in previous linkage analyses for other substance dependence phenotypes. © 2009 WileyLiss, Inc.

Ethanol-induced dopamine (DA) release in the mesolimbic system may reinforce excessive alcohol intake and the progression of alcohol dependence. Within this reward system, the DA transporter (DAT1) plays a key role in the regulation of dopaminergic neurotransmission through presynaptic DA reuptake.

BACKGROUND An inverted region on chromosome 17 has been previously linked to many Pick complex diseases. Due to the inversion, an exact causal locus has been difficult to identify, but the microtubule-associated protein tau gene is a likely candidate gene for its involvement in these diseases with tau inclusion. OBJECTIVE To search for variants that confer susceptibility to 4 tauopathies and clinically related disorders. DESIGN Genomewide association study. SETTING University research laboratory. PARTICIPANTS A total of 231 samples were genotyped from an unrelated white population of patients with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia, and frontotemporal dementia with amyotrophy. Unaffected individuals from the same population were used as controls. MAIN OUTCOME MEASURES The results from an inverted region of chromosome 17 that contains the MAPT gene. Genotypes of cases and controls were compared using a Fisher exact test on a marker-by-marker basis. Haplotypes were determined by visually inspecting genotypes. RESULTS Comparing any particular disease and controls, the association was constant across the inverted chromosome segment. Significant associations were seen for PSP and PSP combined with CBD. Of the 2 haplotypes seen in the region, H1 was overrepresented in PSP and CBD cases compared with controls. CONCLUSIONS As expected, the markers are highly correlated and the association is seen across the entire region, which makes it difficult to narrow down a disease-causing variant or even a possible candidate gene. However, considering the pathologic abnormalities of these diseases and the involvement of tau mutations seen in familial forms, the MAPT gene represents the most likely cause driving the association.Arch Neurol. 2008;65(11):1473-1478--

Alcohol dependence is one of the leading causes of morbidity and mortality in Native Americans. Externalizing disorders such as conduct disorder CD and antisocial personality disorder ASPD have been demonstrated to have significant comorbidity with alcohol dependence in the general population. This studys aims were to: assess the comorbidity of DSMIIIR ASPD and CD with alcohol dependence, to map susceptibility loci for ASPD and CD, and to see if there is overlap with loci previously mapped for alcohol dependence phenotypes in 587 American Indians. Alcohol dependence was found to be comorbid with DSMIIIR ASPD but not CD. However, the amount of alcohol dependence in the population attributable to ASPD andor CD is low. ASPD and the combined phenotype of participants with ASPD or CD were both found to have significant heritability, whereas no significant evidence was found for CD alone. Genotypes were determined for a panel of 791 microsatellite polymorphisms in 251 of the participants. Analyses of multipoint variance component LOD scores, for ASPD and ASPDCD, revealed six locations that had a LOD score of 2.0 or above: on chromosome 13 for ASPD and on chromosomes 1, 3, 4, 14, 17, and 20 for ASPDCD. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies for externalizing diagnoses. These results also further identify new regions of the genome, that do not overlap with alcohol dependence phenotypes previously identified in this population, that may be unique to either the phenotypes evaluated or this population of American Indians. © 2008 WileyLiss, Inc.

Background: In several national surveys, a younger age of onset of first drink and/or regular drinking has been associated with a higher likelihood of the development of alcohol dependence. Some studies have suggested that age at first drink is primarily an environmentally driven variable whereas others suggest that it may be partially mediated by a general vulnerability to exhibit problem behaviors. Although Native Americans, overall, have the highest prevalence of alcohol dependence of any U.S. ethnic group, the relationship of age of onset of intoxication with alcohol dependence in Native American populations is relatively unknown.

Genome‐wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter‐marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19). © 2006 Wiley‐Liss, Inc.

Abstract: Background: Alcohol consumption and alcoholism are heritable traits. Previous linkage analyses for alcoholism and related traits have identified several putative susceptibility loci. In this paper we use, for the first time, linkage analysis to search for alcoholism‐related phenotypes in a family sample selected for smoking behavior.

To estimate the heritability of substance dependence and associated symptoms in a sample of Southwest California (Mission) Indians.

Alcohol dependence is a leading cause of morbidity and mortality in Native Americans, yet etiologic factors contributing to the disorder remain obscure. Complex psychiatric disorders may be influenced by a number of genes that may be difficult to detect because each has a small effect on a disorder that is broadly defined within a social context. However, such genes might be detected if they have a major effect on a more narrowly defined phenotype. Underlying alcohol dependence are appetitive drive states or instincts that lead to drug ‘craving’, contribute to compulsive drug usage, and influence relapse following abstinence. A whole genome scan in Mission Indian families provides evidence for genetic linkage to ‘craving for alcohol’ on chromosome 5. Identification of genes contributing to alcohol craving may give clues to the etiology of the disorder and also provide targets for the development of new medications to treat alcohol dependence.

Background: The University of California, San Francisco (UCSF) Family Alcoholism Study is a project designed to identify genetic loci that influence susceptibility to alcohol dependence and related phenotypes. Evidence supports a substantial genetic contribution to alcoholism susceptibility. However, the genetic epidemiology of alcoholism is complex, and its clinical manifestation is heterogeneous, making phenotype definition and demonstration of linkage difficult. Despite these challenges, some progress has been made toward identifying genes.

Alcohol dependence is a leading cause of morbidity and mortality in Native Americans, yet biological factors underlying the disorder in this ethnic group remain illusive. This study's aims were to map susceptibility loci for DSM‐III‐R alcohol dependence and two narrower alcohol‐related phenotypes in Mission Indian families. Each participant gave a blood sample and completed an interview using the Semi‐Structured Assessment for the Genetics of Alcoholism (SSAGA) that was used to make alcohol dependence diagnoses and the narrower phenotypes of withdrawal, and drinking severity. Genotypes were determined for a panel 791 microsatellite polymorphisms. Analyses of multipoint variance component LOD scores for the dichotomous DSM‐III‐R phenotype revealed no peak LOD scores that exceeded 2.0 at any chromosome location. Two chromosomes, 4 and 12, had peak LOD scores that exceeded 2 for the alcohol use severity phenotype and three chromosomes 6, 15, 16 were found to have peaks with LOD scores that exceeded 2 for the withdrawal phenotype. Evidence for linkage to chromosomes 4 and 15, and 16 have been reported previously for alcohol related phenotypes whereas no evidence has as yet been reported for chromosomes 6 and 12. Combined linkage and association analysis suggest that alcohol dehydrogenase 1B gene polymorphisms are partially responsible for the linkage result on chromosome 4 in this population. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies in alcoholism and further identify new regions of the genome that may be unique to either the restricted phenotypes evaluated or this population of Mission Indians. © 2004 Wiley‐Liss, Inc.

We describe eight members from two large Amish kindreds who share a phenotype characterized by early‐onset pigmentary retinopathy and myopia, global developmental delay and mental retardation, microcephaly, short stature, hypotonia, joint hyperextensibility, small hands and feet, common facial appearance, and friendly disposition. Several of the children had intermittent granulocytopenia. The phenotypic occurrence in three siblings coupled with the increased coefficient of inbreeding in the Amish suggested that this disorder is autosomal recessive and due to a single founder allele. Despite similarity to the clinical features of Cohen syndrome, experienced dysmorphologists attending the 23rd David W. Smith Workshop suggested the facial gestalt of the Amish children was inconsistent with this diagnosis. We mapped the locus responsible for these individuals' phenotype to chromosome 8q22‐q23, which contains the recently discovered Cohen syndrome gene, COH1. Complete sequencing of the COH1 gene identified a likely disease‐causing frameshift mutation and a missense mutation in the Amish patients. A comparison of features among different Cohen syndrome populations with shared linkage to the COH1 locus or known COH1 gene mutations may allow for the determination of improved clinical criteria on which to suspect the diagnosis of Cohen syndrome. We conclude that facial gestalt seems to be an unreliable indicator of Cohen syndrome between ethnic populations, although it is quite consistent among affected individuals within a particular ethnic group. Other features common to almost all individuals with proven COH1 mutations, such as retinal dystrophy, myopia, microcephaly, mental retardation, global developmental delay, hypotonia, and joint hyperextensibility appear to be better clinical indicators of this disorder. © 2004 Wiley‐Liss, Inc.

In autosomal dominant acute necrotizing encephalopathy (ADANE), apparently healthy children develop necrotizing lesions in their thalami and brainstems in the course of febrile illnesses. We used DNA from affected subjects and obligate carriers to map ADANE to a 6.5Mb region on chromosome 2. Sequencing of four candidate genes in the interval (BCL2L11, ST6GalII, CHT1, and FLJ20019), involved in apoptosis, viral recognition, choline transport, and electron transport, showed no disease causing mutations.

In autosomal dominant acute necrotizing encephalopathy (ADANE), apparently healthy children develop necrotizing lesions in their thalami and brainstems in the course of febrile illnesses. We used DNA from affected subjects and obligate carriers to map ADANE to a 6.5Mb region on chromosome 2. Sequencing of four candidate genes in the interval (BCL2L11, ST6GalII, CHT1, and FLJ20019), involved in apoptosis, viral recognition, choline transport, and electron transport, showed no disease causing mutations.

Abstract: Background: Recruiting a large number of participants meeting strict inclusion criteria can be challenging, particularly when selecting for a condition associated with a social stigma such as alcoholism, when participation involves collection of medical specimens and sensitive information, and when the participation of family members or other collaterals is required. Developing and implementing a successful recruitment plan depends upon identifying the most effective recruitment strategies given the available resources.

Background: A low level of response (LR) to alcohol seems to relate to a substantial proportion of the risk for alcoholism and to have significant heritability.

Dementia is typically thought of as a disease caused by the process of aging. Few studies have addressed the premorbid neuropsychological alterations in subjects at risk for the disease–an issue of great importance for the understanding and treatment of degenerative dementias. We used knowledge of the mutation carrier status in a family with inherited dementia to address this issue more efficiently than is possible in the general population, or in cases of inherited dementia where the mutational basis is unknown. Standard neuropsychological tests were used to detect evidence of dysfunction in frontal executive systems in 10 presymptomatic subjects with known mutation carrier status in the highly penetrant condition, frontotemporal dementia and parkinsonism linked to chromosome 17. Presymptomatic carriers demonstrated cognitive dysfunction that was not present in 6 nonmutation‐carrying relatives. Strikingly, frontal– executive dysfunction was apparent in some of the youngest mutation carriers many decades prior to the predicted onset of dementia. Thus, this dysfunction may reflect the native cognitive capacities of affected subjects. These results suggest a potentially important neurodevelopmental component to a dementing condition that has been predominantly considered to be a disease of aging; accordingly, this issue warrants study in other families to assess the applicability of these findings.

Frontotemporal dementia is a heterogeneous, often inherited disorder that typically presents with the insidious onset of behavioral and personality changes. Two genetic loci have been identified and mutations in tau have been causally implicated in a subset of families linked to one of these loci on chromosome 17q21‐22. In this study, linkage analysis was performed in a large pedigree, the MN family, suggesting chromosome 17q21‐22 linkage. Mutational analysis of the tau coding region identified a C‐to‐T change in exon 10 that resulted in the conversion of proline to a leucine (P301L) that segregated with frontotemporal dementia in this family. The clinical and pathological findings in the MN family emphasize the significant overlap between Pick's disease, corticobasal degeneration, and frontotemporal dementia and challenge some of the current dogma surrounding this condition. Pathological studies of two brains from affected members of Family MN obtained at autopsy demonstrate numerous tau‐positive inclusions that were most prominent in the frontal lobes, anterior temporal lobes, and brainstem structures, as well as Pick‐like bodies and associated granulovacuolar degeneration. These Pick‐like bodies were observed in 1 patient with motor neuron disease. Because exon 10 is present only in tau mRNA coding for a protein with four microtubule binding repeats (4R), this mutation should selectively affect 4Rtau isoforms. Indeed, immunoblotting demonstrated that insoluble 4Rtau is selectively aggregated in both gray and white matter of affected individuals. Although there was significant pathological similarity between the 2 cases, the pattern of degenerative changes and tau‐positive inclusions was not identical, suggesting that other genetic or epigenetic factors can significantly modify the regional topology of neurodegeneration in this condition. Ann Neurol 1999;45:704–715

Dopa–responsive dystonia (DRD) is an autosomal–dominant neurological disorder which appears to result from a genetically determined deficiency of striatal dopamine. Pathological evidence suggests that this may be due to the establishment of a reduced number of dopaminergic nerve terminals in the striatum, or to an excessive reduction (pruning) of these terminals in early development. We have mapped the DRD gene to chromosome 14 by linkage analysis in 3 families with a maximum 2–point lod score of 4.67 at 8.6 centiMorgans from D14S63 maximum multipoint lod scores >6 were obtained for the intervals D14S47–D14S52 and D14S52–D14S63. The flanking loci D14S47 and D14S63 define a region of about 22 cM as containing the DRD gene.

There is strong evidence for a genetic contribution to epilepsy, but it is commonly assumed that this genetic contribution is limited to ‘generalized’ epilepsies, and that most forms of ‘partial’ epilepsy are nongenetic. In a linkage analysis of a single family containing 11 affected individuals, we obtained strong evidence for localization of a gene for partial epilepsy. This susceptibility gene maps to chromosome 10q, with a maximum two–point lod score for D10S192 of 3.99 at θ=0.0. All affected individuals share a single haplotype for seven tightly linked contiguous markers; the maximum lod score for this haplotype is 4.83 at θ=0.0. Key recombinants place the susceptibility locus within a 10 centimorgan interval.

Frontotemporal dementia (FTD) is the most common syndrome in which the focus of neurodegeneration is the frontal lobes. FTD is frequently familial. It is also often due to a susceptibility locus on chromosome 17q21-22. Some 17q21-22-linked families have mutations in the tau gene and most have microscopically visible aggregates of hyperphosphorylated tau. Demonstrating that mutations in tau can produce neurodegeneration will necessitate a reassessment of the role of tau in the pathogenesis of the many diseases in which tau biology is disrupted.

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