The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease

Abstract

Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.

TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease

“…Within studies examining cognitive decline in nonpathological ageing populations [19][20][21][22] and in cohorts of individuals with AD 17,18 , the mitochondrial variant TOMM40 '523' has been implicated with mixed results. By comparison, two studies have found no association between the TOMM40 '523' and PD risk 32,33 , while a third group found that the L/VL '523' genotype was overrepresented in Swedish PD patients when compared to controls 31 . However, research into whether TOMM40 '523' alleles play a role in modulating cognitive impairment and rate of decline within PD is profoundly scant, with only a single cross-sectional study of a In past literature, case-control analysis has found that while TOMM40 '523' does not modulate or influence the risk of developing PD, it may affect the age at which symptoms develop 32,33 .…”

“…By comparison, two studies have found no association between the TOMM40 '523' and PD risk 32,33 , while a third group found that the L/VL '523' genotype was overrepresented in Swedish PD patients when compared to controls 31 . However, research into whether TOMM40 '523' alleles play a role in modulating cognitive impairment and rate of decline within PD is profoundly scant, with only a single cross-sectional study of a In past literature, case-control analysis has found that while TOMM40 '523' does not modulate or influence the risk of developing PD, it may affect the age at which symptoms develop 32,33 . The findings of the present study provide evidence that polymorphism in TOMM40 '523' may also have significant effects on cognitive decline and progression to PDD, independent of the influence of APOE ε4.…”

“…Our group, along with others, have previously demonstrated that polymorphism at the TOMM40 '523' locus is not a determinant of PD risk, although it may be a modifier of the age of symptom onset [31][32][33] . However, studies examining the possible role of '523' alleles in modulating cognitive decline in PD are fundamentally lacking, with only a single cross-sectional study reporting a lack of association with dementia in a mixed PD and diffuse Lewy body disease (DLB) cohort 34 .…”

Short structural variants as informative genetic markers for ALS disease risk and progression

“…Importantly, changes in the size and composition of both SV/SSVs can have a significant impact on the binding of regulatory elements that modulate RNA processing and gene expression [16]. SSVs have been implicated in many complex diseases, including ALS and other neurodegenerative diseases [17], such as Parkinson's and Alzheimer's disease [18][19][20]. The ability of SSVs to alter gene expression is dependent on their location within and around the gene or intergenic region, with their effects occurring via several mechanisms including the following: influencing the binding of regulatory elements, mRNA splicing and processing, genome folding and higher order structure, and translation.…”