Summary: A new study identifies a genetic variation in a repeat-rich region of the MUC6 gene that may represent a previously unrecognized risk factor for late-onset Alzheimer’s disease.
Source: Oxford University Press USA
A study published in the Journal of Neuropathology & Experimental Neurology reports a genetic locus that could account for a substantial portion of the heritable risk for Alzheimer’s disease.
Late-onset Alzheimer’s disease (LOAD) is the most common form of the condition and carries a considerable heritable component that remains incompletely explained. Limitations of earlier genetic studies—such as incomplete mapping of certain genomic regions and difficulty analyzing highly repetitive sequences—have left gaps in our understanding of the full genetic architecture of Alzheimer’s disease.
Although family and twin studies have long indicated a strong genetic contribution to LOAD, many studies to date have not fully accounted for that heritability. This discrepancy is often called the “missing” or “hidden” heritability problem. For example, a Swedish twin study estimated heritability for LOAD at about 79%, while common variants identified in prior genome-wide studies have explained only an estimated 20% to 50% of that risk. This suggests that additional genetic factors—perhaps in regions difficult to analyze previously—remain to be discovered.
Recent advances in DNA sequencing and analysis techniques have improved the ability to interrogate complex or poorly mapped genomic regions. Leveraging these improvements, the present study examined data from the Alzheimer’s Disease Sequencing Project, analyzing genetic and clinical information from more than 10,000 research participants to search for variants associated with late-onset Alzheimer’s disease.
Initial analyses highlighted genetic polymorphism in a variable number tandem repeat (VNTR) region within an exon of the Mucin 6 (MUC6) gene, adjacent to the AP2A2 gene. VNTRs are segments of DNA composed of short sequence units repeated in tandem; the number of repeats can vary substantially among individuals. Because VNTR regions are highly repetitive and structurally complex, they have often been overlooked or poorly captured by earlier genome-wide association studies.
The authors report that variation in the MUC6 VNTR correlated with increased neurofibrillary tau pathology—measured as phosphorylated tau (pTau) burden—in the neocortex of autopsied subjects. In a cohort of 119 autopsied individuals with quantitative digital pathology data, larger VNTR sizes were associated with greater neocortical pTau pathology. A separate replication cohort of 173 autopsied subjects showed the same pattern, with subjects carrying longer VNTR regions exhibiting more severe pTau accumulation (p = 0.031).
While MUC6 itself is not strongly expressed in the brain, the adjacent gene AP2A2, which encodes a subunit of the adaptor protein complex 2, is expressed in human brain tissue. The study found lower AP2A2 expression in brain samples from individuals with longer MUC6 VNTRs when normalized to AP2B1 expression (p = 0.014). Immunofluorescence analyses further showed that AP2A2 protein frequently colocalized with neurofibrillary tangles in LOAD brains. In contrast, AP2A2 did not colocalize with pTau pathology in progressive supranuclear palsy or with TDP-43 proteinopathy in the samples examined.
Corresponding authors Yuriko Katsumata and Peter Nelson of the University of Kentucky emphasize caution in interpreting these results. As Dr. Nelson notes, the discovery was made in a relatively modest-sized cohort for genetic studies—many large-scale genetic investigations now include hundreds of thousands of participants. This limited sample size means the finding needs independent replication in other datasets, but it also suggests a potentially large effect size for the identified polymorphism given its detectability in this sample.
Source:
Oxford University Press USA
Media Contacts:
Peter T. Nelson – Oxford University Press USA
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The image is in the public domain.
Original Research: Open access
“Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene”. Peter Nelson et al.
Journal of Neuropathology & Experimental Neurology doi:10.1093/jnen/nlz116.
Abstract
Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene
The study identified a LOAD-associated polymorphism within an exon of MUC6 and immediately downstream of AP2A2. PCR analysis confirmed that the MUC6 VNTR region is highly polymorphic in size. In a cohort of 119 autopsied subjects with quantitative digital pathology measures, larger VNTRs were associated with increased severity of neocortical pTau pathology. A replication cohort of 173 autopsied subjects showed a similar association, with longer VNTR regions linked to more pTau pathology (p = 0.031). AP2A2, unlike MUC6, is expressed in human brain, and AP2A2 expression was lower in brain samples from individuals with longer VNTRs (p = 0.014 after normalization to AP2B1). Double-label immunofluorescence revealed frequent colocalization of AP2A2 protein with neurofibrillary tangles in LOAD, but not with pTau proteinopathy in progressive supranuclear palsy or with TDP-43 inclusions. In summary, polymorphism in a repeat-rich region near AP2A2 is associated with neocortical pTau accumulation; because of the region’s unique repetitive structure, previous genome-wide studies likely missed this signal. AP2A2 also commonly colocalized with neurofibrillary tangles in LOAD brain tissue.