Alison Goate

..Genome-wide linkage studies for Alzheimer's disease have implicated several chromosomal regions as potential loci for susceptibility genes...

..A recent study showed a significant haplotype association (H1c) with AD. The current study is an attempt to replicate this association in an independently ascertained cohort...

..The challenge we address is to distinguish among these correlated loci to highlight potential functional variants and prioritize them for follow-up...

..Identifying these factors will lead to a better understanding of the etiology of the disease and provide additional targets for therapeutic intervention...

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..Dr Goate has been a member of many scientific Review Boards and currently serves on the Editorial Boards of several journals...

..Transgenic mice carrying a mutant human APP gene also show age-dependent beta-amyloid (A beta) deposition in the brain. The rate of deposition in these mice can be modified by apolipoprotein E expression...

..Genetic studies in animal models of alcohol-related behaviors have also identified candidate chromosomal regions and potential candidate genes that can be tested in human populations...

..These findings underscore the utility of electrophysiology and neurogenetics in the understanding of cognitive function and the study of brain-related disorders...

..These results remain significant after taking into account alcohol dependence and depression diagnoses in the sample...

..However, this information has not been widely used in gene identification efforts, which have focused on specific disorders diagnosed using traditional psychiatric classification systems...

..To follow up on this linkage region, we systematically screened single nucleotide polymorphisms (SNPs) across a 2 LOD support interval surrounding the alcohol dependence peak...

..However, we cannot rule out the possibility that multiple rare variants that increase APP expression or Abeta production might influence the risk for LOAD...

..Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD...

..Recently the genetic polymorphism most widely analyzed in DRD2, Taq1A, has been discovered to reside in a neighboring gene, ankyrin repeat and kinase domain containing 1 (ANKK1), located 10 kb downstream from DRD2...

..Further, none of the genes were located directly under the primary COGA linkage peak, which has implications for association tests following-up linkage peaks...

..Lastly, comprehensive genotyping and in vivo metabolism data are used to demonstrate that genome-wide significant associations between CPD and single nucleotide polymorphisms are the result of synthetic associations...

..Our results provide an illustration of the successful use of endophenotypes to identify genes involved in the predisposition to a complex psychiatric phenotype, a strategy originally proposed by Gottesman and Shields in 1972...

..Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association...

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..Since NCT and APH-1 must first bind in order for presenilin and PEN-2 to stably join the complex, we propose that S632 and W648 are essential for a stable interaction with APH-1...

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..Genetic analyses have identified regions on several chromosomes that are associated with these phenotypes and need to be studied further...

..Our findings provide further support that chromosome 6p contains gene(s) affecting intelligence...

..We did not find any evidence that this single nucleotide polymorphism, or any of six others tested in UBQLN1, increases risk for LOAD...

..Our data suggest that these mutations affect the function of full-length PGRN as well as elastase cleavage of PGRN into GRNs, leading to neurodegeneration...

..Other non-conservative mutations in the invariant P(433)A(434)L(435) sequence also result in a phenotype that is indistinguishable from the aspartate mutants, suggesting a direct involvement of this sequence in gamma-secretase activity...

..A meta-analysis of two promoter SNPs, which combined the data from this study with two previous ones, did not show any association either suggesting that common SNPs in Pin1 do not increase the risk for LOAD...

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..PS2 M239V, its PS1 homolog M233V, and other FAD mutations within transmembrane (TM) 5 of PS1 differentially affect CTFgamma and NICD production suggesting that TM5 of PS are important for gamma-secretase cleavage of APP but not Notch...

..To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism...

..Finally, there is also evidence of an area on chromosome 2 that may reflect a common genetic vulnerability locus to both habitual smoking and alcohol dependence...

..Together, these observations strongly support the hypothesis that the PAL motif contributes to the active site conformation of gamma-secretase and of SPP...

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..001). These findings were not observed for the equivalent non-target case data, suggesting a role for the CHRM2 gene in higher cognitive processing in humans...

..A better understanding of the etiology of nicotine addiction may help to increase the success rate of cessation and to decrease the massive morbidity and mortality associated with smoking...

..Uncovering the genes influencing brain oscillations provides a better understanding of the neural function involved in information processing...

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..While regressing out the effect of alcoholism does not affect the linkage findings, the epistatic interactions become statistically insignificant...

..We propose that gamma-secretase contains a PS dimer in its catalytic core, that binding of substrate is at a site separate from the active site, and that substrate is cleaved at the interface of two PS molecules...

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..These results show the importance of common genetic variants that effect exonic splicing suppressor and ESEs to explain human variation regarding clinically-relevant phenotypes...

..Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease...

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..These families were recruited as part of the Collaborative Study on the Genetics of Alcoholism (COGA)...

..Of the seven markers we tested in family-based and case control samples, the only nominally positive association we found was with the 167 bp allele of marker D10S1217 (chi-square=7.11, P=0.045, df=1)...

..Three control subjects were found to be expansion carriers, and no expansions were found among patients, suggesting that C9ORF72 expansions are not a common cause of PD...

..We utilized NGS to identify rare and pathogenic variants in APP, PSEN1, PSEN2, GRN, and MAPT in an Ibero-American cohort...

..In this review, we discuss the challenges associated with harmonizing alcohol-consumption data from studies with widely different assessment instruments, with a particular focus on large-scale genetic studies...

..The advent of genomics and proteomics and a fuller understanding of gene regulation, will open new horizons on the critical electrical events so essential for human brain function...

..The program has been applied to the identification of variants of proteins of biological interest, including APP cleavage products and iPLA(2)beta, and such applications demonstrate the utility of this approach...

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..We hope these recommendations will boost research progress in AD and increase the likelihood of developing effective therapies in the near future...

..We also briefly discuss the effects finding APP mutations has had on our own careers and those of our colleagues from 1991...

..Future studies should examine the linkage and association of psychosis with genetic variation within these families...

..Eight polymorphisms spanning the entire gene were examined using case control (CC) and family-based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data...

..The transmembrane protein Nicastrin has been found to associate with Presenilin, Notch, and APP. Recent biochemical and genetic studies have focused on elucidating the function of this protein...

..These findings provide strong evidence that variants within or close to the CHRM2 locus influence risk for two common psychiatric disorders...

..A challenging problem after a genome-wide association study (GWAS) is to balance the statistical evidence of genotype-phenotype correlation with a priori evidence of biological relevance...

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..Despite accumulating evidence that there is a genetic basis for cannabis use disorders (ie, abuse and dependence), few studies have identified genomic regions that may harbor biological risk and protective factors...

..Mutations in presenilin 1 (PSEN1) are known to cause AD and change Abeta levels. In this study, we have investigated DNA sequence variation in the presenilin (PSEN1) gene using CSF Abeta levels as an endophenotype for AD...

..5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity...

..The perceived bitterness of PROP has also been associated with oral sensation and drinking behaviors...

..This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community...

..Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies...

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..The identification of these specific subhaplotypes that modify risk for PSP/CBD supports the hypothesis that a pathogenic allele exists in a subgroup of PSP patients...

..We describe herein a kindred with very early-onset FAD (age, <40 years) with unusual pathological features and a novel mutation in the presenilin 1 (PSEN1) gene (S170F) and review the existing literature on very early-onset FAD...

..Fine mapping of this linkage region may reveal variants contributing to heaviness of smoking, which will lead to a better understanding of the genetic mechanisms underlying nicotine dependence...

..Application of conditional analyses is potentially useful in larger sample collections to identify susceptibility genes of modest influence that may not be identified in a genome-wide scan aimed to identify single gene effects...

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..The P117A variant is a novel mutation in PSEN1, which causes early-onset AD in an autosomal dominant manner...

..This study is the first to our knowledge to demonstrate that genetic and environmental factors influence age of onset in a kindred with a familial AD mutation...

..The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration...

..6%), whereas 45% of African Americans carry the allele (MAF 26%), which makes it a much more significant risk factor in the African American population...

..0 on chromosome 2 (3.2, 234 cM), 10 (2.4 and 2.6 at 60 cM and 116 cM) and 13 (2.1 at 64 cM). These regions may harbor genes that contribute to the biological basis of alcohol and drug dependence...

..In this article, the authors will review the progress in understanding the pathogenic implications of the genes mutated in familial early onset AD and the mapping studies to identify additional genes involved in late-onset AD...

..Lack of transcleavage by wtPS1 suggests that PS1 endoproteolysis occurs via intramolecular cleavage and does not require dimerization...

..Women are at higher risk than men for neurologic complications from cardiac operations. This study identified risk factors for neurocognitive dysfunction after cardiac operations in elderly women...

..These results suggest that cleavage at the gamma40/42- and the S3-like sites can be dissociated, and that APP signaling and Abeta production are not tightly linked...

..Putative risk alleles/haplotypes will be tested for a functional effect on A-Beta levels in an in vitro model. Risk alleles will be characterized in several populations to determine their importance. ..

..Putative risk alleles/haplotypes will be tested for a functional effect on Abeta levels in an in vitro model. Risk alleles will be characterized in several populations to determine their importance. ..

..The use of case-control and endophenotype measures in CSF provides a powerful and novel approach to the genetics of LOAD. ..

..Finally, we will complete a 20cM genome screen in the replication sample increasing the effective sample size to 600 sib pairs, enabling us to look for genes of smaller effect size. ..

..We also anticipate that these studies will increase our understanding of the Notch signaling, a process that is important not only for many developmental decisions but for cancer as well. ..

..The goal of the present study is to identify genetic risk factors for Alzheimer's disease, which in the longer term may lead to novel drug targets and improved treatment/prevention of the disease. ..