Yu, C. E., Seltman, H., Peskind, E. R., Galloway, N., Zhou, P. X., Rosenthal, E. et al. Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimer's disease: patterns of linkage disequilibrium and disease/marker association. Genomics 89, 655-665

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Genomics (Impact Factor: 2.28). 07/2007; 89(6):655-65. DOI: 10.1016/j.ygeno.2007.02.002
Source: PubMed


The epsilon(4) allele of APOE confers a two- to fourfold increased risk for late-onset Alzheimer's disease (LOAD), but LOAD pathology does not all fit neatly around APOE. It is conceivable that genetic variation proximate to APOE contributes to LOAD risk. Therefore, we investigated the degree of linkage disequilibrium (LD) for a comprehensive set of 50 SNPs in and surrounding APOE using a substantial Caucasian sample of 1100 chromosomes. SNPs in APOE were further molecularly haplotyped to determine their phases. One set of SNPs in TOMM40, roughly 15 kb upstream of APOE, showed intriguing LD with the epsilon(4) allele and was strongly associated with the risk for developing LOAD. However, when all the SNPs were entered into a logit model, only the effect of APOE epsilon(4) remained significant. These observations diminish the possibility that loci in the TOMM40 gene may have a major effect on the risk for LOAD in Caucasians.

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Available from: Chang-En Yu, May 28, 2015
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    • "These effects may trigger a vicious cycle where damaged mitochondria can generate Aβ and Aβ can then enter mitochondria and exacerbate damage. Interestingly , amyloid is imported into mitochondria by translocase of the outer membrane (TOM) machinery [207], and TOMM40, which encodes the channel protein subunit of the translocase of the outer mitochondrial membrane (TOMM) complex [208] is in high linkage disequilibrium with APOE [209]. This makes it difficult to discern which gene actually contributes to AD risk. "
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    ABSTRACT: Although Alzheimer's Disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease -modifying therapies.
    Full-text · Article · Apr 2014 · Biochimica et Biophysica Acta
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    • "Several SNPs in the APOE and TOMM40 genes are in strong linkage disequilibrium; for example, rs429358 and 36 SNPs within AE1.17 KB of the APOE region including 15 TOMM40 SNPs; average D 0 ¼ 0.91, r 2 ¼ 0.22, n ¼ 1262 (Yu et al., 2007). The TOMM40 locus encodes for a channel-forming subunit of the translocase of the outer mitochondrial membrane complex (Humphries et al., 2005). "
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    ABSTRACT: Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 ("523") variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640-650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ε4 "risk" allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ε3/ε4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 "short" allele showed lower white matter integrity when compared with carriers of the "long" and "very-long" alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.
    Full-text · Article · Jan 2014 · Neurobiology of aging
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    • "These observations indicated that the associations of the two SNPs in the TOMM40 gene, proximal to APOE, with LOAD are most likely a reflection of the effects of the APOE gene. This lack of independent association is consistent with the previous studies (Yu et al. 2007; Cruchaga et al. 2011). Yu et al. reported that one set of SNPs in TOMM40 including rs11556505 were significantly associated with AD risk, but no evidence of independent effect of differential allelic distribution for these SNPs were observed when all these SNPs were entered into a logistic model, while Cruchaga et al. identified that the ''Long'' variant of the PolyT repeat virtually reflected the APOE e4 allele. "
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    ABSTRACT: Mitochondrial dysfunction is an early defect in the pathogenesis of late-onset Alzheimer's disease (LOAD). One interesting candidate gene for mitochondrial dysfunction in LOAD is the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene. Several single nucleotide polymorphisms (SNPs) within TOMM40 have been shown to affect susceptibility to LOAD in Caucasians, while there are no studies on the association of the polymorphisms with LOAD risk in Han Chinese. Here, the association of TOMM40 polymorphisms in LOAD was investigated in a large Northern Han Chinese cohort consisting of 1,578 individuals. Both allelic and genotypic associations of three SNPs (rs157580, rs2075650, and rs11556505) with LOAD risk were observed in the total sample as well as in the non- APOE ε4 carriers. For rs1160985, the allele and genotype frequencies differed significantly only in APOE ε4 carriers. After adjustment for age, gender, and APOE ε4 status, the association remained statistically significant only for the rs157580 but not for rs2075650 and rs11556505. In contrast, the rs1160985 exhibited significant risk effect after adjustment. In addition, haplotype analysis confirmed that the haplotypes derived from SNPs in rs2075650, rs11556505, and rs1160985 were associated with either risk or protective effects. In summary, our findings suggest that the TOMM40 polymorphisms may play a role in the pathogenesis of LOAD in Han Chinese.
    Full-text · Article · Jan 2013 · Neuromolecular medicine
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