Examination of Candidate Exonic Variants for Association to Alzheimer Disease in the Amish

Abstract

Alzheimer disease (AD) is the most common cause of dementia. As with many complex diseases, the identified variants do not explain the total expected genetic risk that is based on heritability estimates for AD. Isolated founder populations, such as the Amish, are advantageous for genetic studies as they overcome heterogeneity limitations associated with complex population studies. We determined that Amish AD cases harbored a significantly higher burden of the known risk alleles compared to Amish cognitively normal controls, but a significantly lower burden when compared to cases from a dataset of unrelated individuals. Whole-exome sequencing of a selected subset of the overall study population was used as a screening tool to identify variants located in the regions of the genome that are most likely to contribute risk. By then genotyping the top candidate variants from the known AD genes and from linkage regions implicated previous studies in the full dataset, new associations could be confirmed. The most significant result (p = 0.0012) was for rs73938538, a synonymous variant in LAMA1 within the previously identified linkage peak on chromosome 18. However, this association is specific to the Amish and did not generalize when tested in a dataset of unrelated individuals. These results suggest that additional risk variation in the Amish remains to be identified and likely resides outside of the classical protein coding gene regions.

Identification of Methylated Gene Biomarkers in Patients with Alzheimer’s Disease Based on Machine Learning

“…Lavorgna and Harhaj found that STAMBPL1 regulated NF-κB activation in neuroinflammation process [33]. It is worth mentioning that the missense mutation of STAMBPL1 has been found in AD in the Amish [7]. In this study, we also found the relationship between STAMBPL1 and AD, which further suggested that STAMBPL1 may be a crucial factor in the pathology of AD.…”

“…The risk of genetic component of AD has been evidenced by the increased risk of AD among first-degree relatives of affected patients [6]. There are several other risk factors associated with AD, such as aging, age, activity, lifestyle, education, family history, and atherosclerosis [7]. Along with the progressively incapacitating, AD can linger many years.…”

Multivariate genome wide association and network analysis of subcortical imaging phenotypes in Alzheimer’s disease

“…Table 4 shows that the top 10 gene-level findings identified by MGAS, where APOE ( p = 2.77E-08), TOMM40 ( p = 3.49E-08), and APOC1 ( p = 2.09E-06) are the well-known AD risk regions. LAMA1 ( p = 3.79E-05) was reported to encode the laminin alpha subunit associated with late onset AD in the Amish [ 22 ]. HSD17B7P2 ( p = 8.40E-05) was reported to play an important role in brain development [ 23 ].…”

Linkage analysis of multiplex Caribbean Hispanic families loaded for unexplained early‐onset cases identifies novel Alzheimer's disease loci

“…There is strong evidence that cerebrovascular dysregulation plays a role in neurodegeneration and AD [47] . A recent whole-exome sequencing study in the Amish population identified a synonymous variant in LAMA1, rs73938538 [48] . PTPRM encodes protein tyrosine phosphatase, receptor type M, a member of the protein tyrosine phosphatase (PTP) family.…”