Genome scan on Swedish Alzheimer's disease families

Abstract

Alzheimer's disease (AD) is an age-related disease, which affects approximately 40% of the population at an age above 90 years. The heritability is estimated to be greater than 60% and there are rare autosomal dominant forms indicating a significant genetic influence on the disease process. Despite the successes in the early 1990s when four genes were identified, which directly cause the disease (APP, PSEN1 and PSEN2) or greatly increase the risk of disease development (APOE), it has proved exceedingly difficult to identify additional genes involved in the pathogenesis. However, several linkage and association studies have repeatedly supported the presence of susceptibility genes on chromosomes (chrms) 9, 10 and 12. The study populations have, however, mostly been of great genetic heterogeneity, and this may have contributed to the meagre successes in identifying the disease associated genetic variants. In this study, we have performed a genome wide linkage study on 71 AD families from the relatively genetically homogeneous Swedish population where it is also possible to study the genetic ancestry in public databases. We have performed nonparametric linkage analyses in the total family material as well as stratified the families with respect to the presence or absence of APOE varepsilon4. Our results suggest that the families included in this study are tightly linked to the APOE region, but do not show evidence of linkage to the previously reported linkages on chrms 9, 10 and 12. Instead, we observed the next highest LOD score on chromosome 5q35 in the total material. Further, the data suggest that the major fraction of families linked to this region is APOE varepsilon4 positive.

Expanded high-resolution genetic study of 109 Swedish families with Alzheimer's disease

“…28 A little surprisingly, the only significant linkage peak obtained by mpt analysis in the full set of 109 Swedish AD families (mpt LOD ¼ 5.05, P ¼ 0.015) was still a reflection of the known APOE gene in chromosome 19q13. Sixty-three of the 109 families (58%), in which all affected carried at least one e4 allele, generated a significant mpt LOD of 5.31 at a distance of 0.35 cM centromeric to the APOE gene even in the absence of the APOE genotypes in the analysis.…”

“…In this study, we genotyped 1102 microsatellite markers in 486 individuals from 109 AD families with a success rate of 96%, and possible genotyping errors were minimized by checking for Mendelian inconsistencies before starting the linkage analysis. These genotypes were combined with the non-redundant genotypes from our previous study, 28 resulting in information from a total of 1289 genotyped markers. All linkage data presented in table format were acquired without the APOE genotypes.…”

“…27 Recently, we published the first Swedish genome-wide scan on 71 AD families (GS1) and found a significant linkage peak corresponding to the APOE region in chromosome 19q13. 28 In the present study (GS2), we have added additional affected and unaffected individuals to the original 71 families as well as 38 novel families and increased the density of genotyped markers (from an average intermarker distance of 8.97 cM to one marker per 2.85 cM) by genotyping 1102 novel microsatellites. Thus, we report the results from a genome-wide linkage analysis based on the data generated by genotyping 1289 markers on 468 individuals from 109 Swedish AD families.…”

Review article What causes alzheimer’s disease?

“…Late-onset AD (LO-AD) is likely to be a multifactorial disease with the potential involvement of multiple genes. Hence, genome wide studies have revealed genes on chromosomes 6, 9, 10, 11, 12, 14, 18, 19, and the X chromosome could be involved in AD [44,176] with the most compelling case for a gene on chromosome 12 [138]. Further studies map this locus to 12q13, a region which encompasses the vitamin D receptor (VDR) gene [200].…”

Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia

“…9p, 9q, 10q, 12p and 19q. [20][21][22][23][24] Extensive follow-up and fine mapping studies have been performed in these linked genetic regions without identifying a new AD gene. [25][26][27][28][29][30][31][32][33] A summary of all reported genetic linkage and association studies for AD is available in the AlzGene database.…”