Assess the impact of common human TMEM173 alleles on Alzheimer's disease

Objectives: Affecting more than 3 million people per year, Alzheimer's Disease is the only leading cause of death without a treatment or cure. Genetics plays a major role in developing Alzheimer's Disease. For example, APOEe4 is the strongest genetic risk factor for sporadic Alzheimer's disease. The APOEe4 allele increases the disease risk by 3 times in heterozygotes and by 15 times in homozygotes. Notably, - 40% of African Americans have at least one APOEe4 allele. Yet, African Americans with APOE e4 do not have an elevated risk of developing Alzheimer's. The underlying protective mechanism in Africans is unknown. The TMEM173 gene encodes a protein called STING that is critical in host defense, anti-tumor immunity, and tissue inflammation. Besides the WT allele, the human TMEM173 gene contains two additional common alleles: R71H­G230A-R293Q (HAQ) and G230A-R293Q (AQ). In East Asians, WT/HAQ (34.3%), not WT/WT (22.0%), is the most common TMEM173 genotype. Intriguingly, the AQ allele is exclusively carried by Africans (~40%). The objective is to explore/establish an association between the common African AQ allele and protection against Alzheimer’s Disease.
Study design: Our hypothesis is that the common African-specific TMEM173 AQ allele is associated with a decreased risk of Alzheimer’s disease. Using the Data Portal, https://dss.niagads.org/datasets/, we will select the relevant dataset. For example, one of the datasets we are interested in is (https://dss.niagads.org/sample-sets/snd 10003/) ADGC African American samples (Accession Number:snd 10003) that has 1648 controls and 1290 cases. We will download the sequence file, analyze the TMEM173 alleles in the 1648 controls and 1290 cases data, calculate the odds ratio with p values, and determine if the TMEM173 AQ alleles impact AD incidence in Africans. We will also compare ADSP cohorts with Caucasians, Asians, and Hispanics for the common TMEM173 alleles.
Analysis plan: The analyzed cohorts consist of cases and controls. We will compare the allele frequency differences in the case and controls. We will match gender, age, and APOE e4 allele but will not conduct detailed phenotypic characterization.

Genetic factors influence people with Alzheimer’s. For example, just one copy of the APOEe4 allele increases the odds of Alzheimer’s disease by ~3 folds. - 40% of Africans have at least one copy of APOEe4 allele. Yet, Africans with APOEe4 do not have an elevated risk of developing Alzheimer's. The underlying protective mechanism is unknown. Accumulating evidence suggests that the TMEM173 gene promotes neuroinflammation and neurodegeneration, such as Parkinson’s and Alzheimer’s diseases. Intriguingly, while the majority of people have the WT allele of the TMEM173 gene, many have the R71H-G230A-R293Q (HAQ), G230A-R293Q (AQ) alleles. More East Asians are WT/HAQ (34.3% of East Asians) than WT/WT (22.0%). Meanwhile, the AQ allele is Africans-specific. Less than 1% of non-Africans have the AQ allele, while ~40% of Africans carry the AQ allele. One copy of the AQ allele can functionally suppress TMEM173-promoted tissue inflammation in mice. Here, we explore the potential protective role of the AQ allele in Alzheimer’s disease.