LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry

Abstract

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Keywords: KCNMB2; Dementia; Diversity; Epidemiology; FTLD; Genome-Wide Association Studies (GWAS); KATP.

Figure 1.

Allele frequencies for single nucleotide variants (SNVs) associated with LATE-NC phenotype(s) in persons of European (blue) or African (orange) ancestry. For the identity of the specific increased risk-associated allele, see Table 1. Risk alleles are rs1990622 (TMEM106B), rs5848 (GRN), rs1914361 (ABCC9), and rs704178 (ABCC9). As the plots and Table 1 indicate, there were n = 5 cohorts for European ancestry and n = 7 cohorts for African ancestry.

Figure 2.

Principal components (A) and Uniform Manifold Approximation and Projection (UMAP) plots (B) for participants in the present study (Table 1), colored by self-identified race. African and European ancestries were identified based on UMAP plot.

Figure 3.

In persons of African ancestry (A) and European ancestry (B), LocusZoom plots shown for associations between single nucleotide polymorphisms in ABCC9 and hippocampal sclerosis with linkage disequilibrium (LD) depicted below in heatmap plots. A signal at rs1914361 was evident in the participants of African ancestry, whereas in this sample of European ancestry participants, ABCC9 genetic variation was not associated with HS risk.

Figure 4.

In persons of African ancestry (A) and European ancestry (B), LocusZoom plots shown for associations between single nucleotide polymorphisms in TMEM106B and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), with linkage disequilibrium (LD) depicted below in heatmap plots. In this sample of participants of African ancestry, TMEM106B variants were not associated with risk for LATE-NC.