Alzheimer Disease: Avramopoulos D

Hamshere ML, Holmans PA, Avramopoulos D, Bassett SS, Blacker D, Bertram L, Wiener H, Rochberg N, Tanzi RE, Myers A, Wavrant-De Vrièze F, Go R, Fallin D, Lovestone S, Hardy J, Goate A, O'Donovan M, Williams J, Owen MJ. · Biostatistics and Bioinformatics Unit, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. · Hum Mol Genet. · Pubmed #17725986 links to  free full text

Abstract: Previous attempts to identify genetic loci conferring risk for late-onset Alzheimer's disease (LOAD) through linkage analysis have observed some regions of linkage in common. However, due to the sometimes-considerable overlap between the samples, some of these reports cannot be considered to be independent replications. In order to assess the strength of the evidence for linkage and to obtain the best indication of the location of susceptibility genes, we have amalgamated three large samples to give a total of 723 affected relative pairs (ARPs). Multipoint, model-free ARP linkage analysis was performed. Genome-wide significant evidence for linkage was observed on 10q21.2 (LOD=3.3) and genome-wide suggestive evidence was observed on 9q22.33 (LOD=2.5) and 19q13.32 (LOD=2.0). One further region on 9p21.3 was identified with an LOD score>1. We observe no evidence to suggest that more than one locus is responsible for the linkage to 10q21.2, although this linked region may harbour more than one susceptibility gene. Evidence of allele-sharing heterogeneity between the original collection sites was observed on chromosome 9 but not on chromosome 10 or 19. Evidence for an interaction was observed between loci on chromosomes 10 and 19. Where samples overlapped, the genotyping consistency was high, estimated to average at 97.3%. Our large-scale linkage analysis consolidates clear evidence for a susceptibility locus for LOAD on 10q21.2.

Avramopoulos D, Wang R, Valle D, Fallin MD, Bassett SS. · Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. · Neurogenetics. · Pubmed #17334805 No free full text.

Abstract: Alzheimer's disease (AD) is a disabling neurodegenerative disorder with onset commonly in late life. Three genes have been identified causing earlier onset AD, and a fourth has been shown to be a risk factor for late onset AD (LOAD), while many more yet unrecognized genes are thought to contribute to susceptibility. Many studies have reported linkage to LOAD on human chromosome 10, where we have identified a parent of origin effect [Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B Jr, Go RC, Fallin MD. Am J Med Genet B Neuropsychiatr Genet 141:537-540, (2006), Bassett SS, Avramopoulos D, Fallin D. Am J Med Genet 114:679-686, (2002)]. In this paper, we report on a gene in this region that shows reduced expression with increasing age, reduced expression in females across ages, and further reduction in LOAD patients. In concordance with the observed parent of origin effect on the linkage, this reduction is more pronounced in patients with an affected mother. We discovered this gene while studying the alkaline ceramidase gene (ASAH2); it is a partial paralog of ASAH2, and we call it ASAH2L. It is the result of a partial duplication of ASAH2 on chromosome 10q11.23, just downstream from the sequence with promoter activity. ASAH2L has a polymorphic start codon with a single nucleotide change of the original ASAH2 sequence plus other putative translation start sites that might produce novel proteins. It is expressed in all the tissues we tested including the brain and is an interesting example of the generation of a new gene. Comparison of primate and other mammal genomes suggests that ASAH2L is human specific. Further research would be necessary to determine the function of the ASAH2L transcript and explore any possible involvement in neurodegeneration.

Avramopoulos D, Zandi P, Gherman A, Fallin MD, Bassett SS. · Department of Psychiatry, The Johns Hopkins University, School of Medicine, Broadway Research Building 509, 733 North Broadway, Baltimore, MD 21205, USA. · Hum Genomics. · Pubmed #16848972 No free full text.

Abstract: Genes for complex disorders have proven hard to find using linkage analysis. The results rarely reach the desired level of significance and researchers often have failed to replicate positive findings. There is, however, a wealth of information from other scientific approaches which enables the formation of hypotheses on groups of genes or genomic regions likely to be enriched in disease loci. Examples include genes belonging to specific pathways or producing proteins interacting with known risk factors, genes that show altered expression levels in patients or even the group of top scoring locations in a linkage study. We show here that this hypothesis of enrichment for disease loci can be tested using genome-wide linkage data, provided that these data are independent from the data used to generate the hypothesis. Our method is based on the fact that non-parametric linkage analyses are expected to show increased scores at each one of the disease loci, although this increase might not rise above the noise of stochastic variation. By using a summary statistic and calculating its empirical significance, we show that enrichment hypotheses can be tested with power higher than the power of the linkage scan data to identify individual loci. Via simulated linkage scans for a number of different models, we gain insight in the interpretation of genome scan results and test the power of our proposed method. We present an application of the method to real data from a late-onset Alzheimer's disease linkage scan as a proof of principle.

Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B, Go RC, Fallin MD. · Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #16741936 links to  free full text

Abstract: The chromosome 10q region has recently received a great deal of attention in late-onset Alzheimer's disease (LOAD), given the growing evidence of linkage to LOAD, or to A-beta levels, reported by several groups. In a recent paper we reported evidence of linkage in this region in our subset of the NIMH AD genetics initiative pedigrees, approaching genome-wide significance (non-parametric LOD score = 3.27), when only families with maternal disease origin were analyzed [Bassett et al. (2002); Am J Med Genet 114:679-686]. We have now extended this work, using an independent subset of NIMH AD pedigrees from the University of Alabama at Birmingham (UAB), and show further evidence of linkage using parent-of-origin information. As in our Hopkins sample, maternal but not paternal pedigrees show significantly increased linkage in the chromosome 10q region compared to the unstratified sample. Combining data from our previous fine-mapping work on this region and five new markers genotyped in all pedigrees results in a non-parametric LOD score of 3.73 in the same region, a value that reaches genome wide significance for linkage, with an empirical P value = 0.003. These results support our earlier findings and narrow the region of interest. In combination with findings from other groups, these results provide further evidence that this chromosome 10 region harbors a gene implicated in LOAD, and our use of parent-of-origin information has been useful in further narrowing the region of interest.

Bassett SS, Kusevic I, Cristinzio C, Yassa MA, Avramopoulos D, Yousem DM, Fallin MD. · Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA. · Ann Neurol. · Pubmed #15984011 links to  free full text

Abstract: Previously, we reported evidence of genetic heterogeneity in late-onset familial Alzheimer's disease, based on sex of affected parent, demonstrating linkage to chromosome 10q, a region identified by other groups and implicated as a quantitative trait loci for Abeta levels, in families with an affected mother. Using functional magnetic resonance imaging and a memory encoding task, we now show differential brain activation patterns among asymptomatic offspring which correspond to the previous linkage finding. These results suggest the possibility that activation patterns may prove useful as a preclinical quantitative trait related to the putative familial late-onset AD gene in this chromosome 10 region.

Avramopoulos D, Fallin MD, Bassett SS. · The Johns Hopkins University, Department of Psychiatry, School of Medicine, Meyer 4 Room 139, 600 N. Wolfe St, Baltimore, MD 21287, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #15389761 No free full text.

Abstract: Cases of early onset AD have been attributed to three genes, PSEN1, PSEN2, and APP, while the only gene consistently associated with late onset AD (LOAD) is APOE. Several genome scans have now been performed for LOAD with inconsistent findings in several genomic regions, possibly reflecting the underlying genetic heterogeneity. Many lines of evidence suggest that the absence or presence of psychotic symptoms, common in AD, might delineate distinct etiologic disease subtypes. We have performed a genome scan of 148 AD pedigrees (ages of onset more than 50 years) including the presence or absence of delusions and hallucinations as covariates. This approach identified linkage to a locus on chromosome 14q24.3, close to the PSEN1 locus (LOD score 3.91; genome-wide empirical P = 0.052), derived from individuals that do not have co-morbid hallucinations. The finding appears stronger (LOD score 5.74; genome-wide empirical P = 0.048) in families that include younger affected members (AAO between 50 and 65 years), however it is not present without the inclusion of the covariate and we observe no correlation between the presence of hallucinations and the age of onset. A mutation screen of PSEN1 did not detect any coding region or splice site mutations. This linkage finding suggests the presence of a gene causing AD without co-morbid hallucinations and with an earlier (yet not early) age at onset (AAO) in the 14q24 region. This region requires further study to replicate the finding and identify the genetic variant responsible for the linkage.

Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RC, Mahoney A, Beaty T, Fallin MD, Avramopoulos D, Chase GA, Folstein MF, McInnis MG, Bassett SS, Doheny KJ, Pugh EW, Tanzi RE, Anonymous00039. · Massachusetts General Hospital, Charlestown, MA, USA. · Hum Mol Genet. · Pubmed #12490529 links to  free full text

Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

Bassett SS, Avramopoulos D, Fallin D. · Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Am J Med Genet. · Pubmed #12210287 No free full text.

Abstract: Evidence for a parent of origin effect in Alzheimer disease was obtained from a sample of 148 sibships on which affection status of the parents was sought using family history interviews. The parent study recruited families with two or more affected sibs for late onset AD utilizing rigorous diagnostic criteria. In 74 families, there was evidence of an affected parent, 49 maternal and 25 paternal. Genome scan data were analyzed for the sample as a whole and for the maternal and paternal families separately, using Genehunter-ASM. Seven regions with Z(lr) scores >or=2 were identified, four in maternal families (chr. 10,12,19,20) and three in paternal families (chr. 1,7,13). With the exception of the chromosome 10 finding, analysis by parent of origin greatly increased evidence of linkage in areas showing no linkage in the overall analyses. For example, a chr. 12 region reached a LOD = 2.29 among maternal families whereas the same region showed a LOD = 0.3 when all families were analyzed together. The strongest findings among maternal families (chr. 10 and 12) were followed up with fine mapping that resulted in an increase in maximum LOD scores from 2.7-3.2 on chr. 10, and 2.29-2.42 on chr. 12. These analyses highlight the importance of parent of origin effects in late-onset AD families and identify several genomic regions that may include genes linked to late-onset AD specific to disease transmission from the mother and require further investigation.

Petersen MB, Karadima G, Samaritaki M, Avramopoulos D, Vassilopoulos D, Mikkelsen M. · Department of Genetics, Institute of Child Health, Athens, Greece. · Am J Med Genet. · Pubmed #10951459 No free full text.

Abstract: Several lines of evidence suggest a shared genetic susceptibility to Down syndrome (DS) and Alzheimer disease (AD). Rare forms of autosomal-dominant AD are caused by mutations in the APP and presenilin genes (PS-1 and PS-2). The presenilin proteins have been localized to the nuclear membrane, kinetochores, and centrosomes, suggesting a function in chromosome segregation. A genetic association between a polymorphism in intron 8 of the PS-1 gene and AD has been described in some series, and an increased risk of AD has been reported in mothers of DS probands. We therefore studied 168 probands with free trisomy 21 of known parental and meiotic origin and their parents from a population-based material, by analyzing the intron 8 polymorphism in the PS-1 gene. An increased frequency of allele 1 in mothers with a meiosis II error (70.8%) was found compared with mothers with a meiosis I error (52.7%, P < 0.01), with an excess of the 11 genotype in the meiosis II mothers. The frequency of allele 1 in mothers carrying apolipoprotein E (APOE) epsilon4 allele (68.0%) was higher than in mothers without epsilon4 (52.2%, P < 0.01). We hypothesize that the PS-1 intronic polymorphism might be involved in chromosomal nondisjunction through an influence on the expression level of PS-1 or due to linkage disequilibrium with biologically relevant polymorphisms in or outside the PS-1 gene.