Does <i>APOE</i> explain the linkage of Alzheimer's disease to chromosome 19q13?

Blom, Elin; Holmans, Peter Alan; Arepalli, Sampath; Adighibe, Omanma; Hamshere, Marian L.; Gatz, Margaret; Pedersen, Nancy L.; Bergem, Astrid Liv Mina; Hollingworth, Paul; Goate, Alison M.; Williams, Julie; Lannfelt, Lars; Hardy, John; Vrièze, Fabienne Wavrant‐De; Glaser, Anna

doi:10.1002/ajmg.b.30681

Cited by 12 publications

(6 citation statements)

References 22 publications

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“…and the Swedish sample contributed considerably to the improved linkage (Table 3 ). The influence of the APOE locus on AD has been correlated to a lower age at onset [ 4 , 24 ], as further demonstrated in our recent analysis of the chromosome 19 linkage [ 25 ]. Accordingly, linkage analysis of the NIMH cohort by Blacker et al .…”

Section: Discussionmentioning

confidence: 83%

Further analysis of previously implicated linkage regions for Alzheimer's disease in affected relative pairs

et al. 2009

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BackgroundGenome-wide linkage studies for Alzheimer's disease have implicated several chromosomal regions as potential loci for susceptibility genes.MethodsIn the present study, we have combined a selection of affected relative pairs (ARPs) from the UK and the USA included in a previous linkage study by Myers et al. (Am J Med Genet, 2002), with ARPs from Sweden and Washington University. In this total sample collection of 397 ARPs, we have analyzed linkage to chromosomes 1, 9, 10, 12, 19 and 21, implicated in the previous scan.ResultsThe analysis revealed that linkage to chromosome 19q13 close to the APOE locus increased considerably as compared to the earlier scan. However, linkage to chromosome 10q21, which provided the strongest linkage in the previous scan could not be detected.ConclusionThe present investigation provides yet further evidence that 19q13 is the only chromosomal region consistently linked to Alzheimer's disease.

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Section: Discussionmentioning

confidence: 83%

Further analysis of previously implicated linkage regions for Alzheimer's disease in affected relative pairs

et al. 2009

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“…This exclusion is due to observations of multiple association signals in neighbouring SNPs to rs429358 and rs7412, believed to be tagging the effect of the isoform SNPs via linkage disequilibrium (LD), therefore large regions of the genome surrounding APOE are often removed prior to PRS analysis to prevent confounding effects of these variants. This excluded region ranges from 14kb to over 2Mb [7][8][9][10][11][12] , despite multiple studies suggesting that additional loci in this region may be having independent effects [13][14][15][16][17][18][19] . Therefore, the removal of this area could be missing key contributory variants from PRS models.…”

Section: Introductionmentioning

confidence: 99%

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2023

J Neurol Neuromedicine

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The APOE gene and particularly the ε4 allele have been a long-established risk factor for Alzheimer's disease (AD), demonstrating the largest genetic effect size in this complex disease. In light of the odds ratios observed for the risk allele, many studies disregard neighbouring association signals as merely "tagging" this effect. Polygenic risk score (PRS) analyses in this field regularly use low linkage disequilibrium parameters (r 2 ≥0.1) when selecting SNPs for analysis across the genome and remove kilobases of data surrounding the APOE locus, preventing confounding factors influencing their results. This study investigated a 500kb region surrounding the APOE locus, utilising PRS analysis to explore whether additional SNPs in this region could be providing contributory effects to AD predictability. The data presented here suggest that the "sphere of influence" of the APOE isoform SNPs covers a region of around 92kb; SNPs in Linkage Disequilibrium (LD) at r 2 <0.4 with rs429358 potentially contribute independently to the PRS predictability for AD, and that there are additional independent SNPs in this region that have increased effects in an APOE ε4 negative sample. This study concludes that further consideration is required when selecting LD parameters for PRS analysis and that additional investigation into the region surrounding APOE may yield polymorphisms that may play a pivotal role in the development of AD.

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Section: Introductionmentioning

confidence: 99%

Utilising Polygenic Risk Score Analysis for AD to Determine the “Sphere of Influence” of the APOE Isoform SNPs

Farrell¹,

Brookes²

2022

J Neurol Neuromedicine

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The APOE gene and particularly the ε4 allele have been a long-established risk factor for Alzheimer’s disease (AD), demonstrating the largest genetic effect size in this complex disease. In light of the odds ratios observed for the risk allele, many studies disregard neighbouring association signals as merely “tagging” this effect. Polygenic risk score (PRS) analyses in this field regularly use low linkage disequilibrium parameters (r2≥0.1) when selecting SNPs for analysis across the genome and remove kilobases of data surrounding the APOE locus, preventing confounding factors influencing their results. This study investigated a 500kb region surrounding the APOE locus, utilising PRS analysis to explore whether additional SNPs in this region could be providing contributory effects to AD predictability. The data presented here suggest that the “sphere of influence” of the APOE isoform SNPs covers a region of around 92kb; SNPs in Linkage Disequilibrium (LD) at r2<0.4 with rs429358 potentially contribute independently to the PRS predictability for AD, and that there are additional independent SNPs in this region that have increased effects in an APOE ε4 negative sample. This study concludes that further consideration is required when selecting LD parameters for PRS analysis and that additional investigation into the region surrounding APOE may yield polymorphisms that may play a pivotal role in the development of AD.

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Does APOE explain the linkage of Alzheimer's disease to chromosome 19q13?

Cited by 12 publications

References 22 publications

Further analysis of previously implicated linkage regions for Alzheimer's disease in affected relative pairs

Further analysis of previously implicated linkage regions for Alzheimer's disease in affected relative pairs

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Utilising Polygenic Risk Score Analysis for AD to Determine the “Sphere of Influence” of the APOE Isoform SNPs

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