The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion

Abstract

Apart from amyloid β deposition and tau neurofibrillary tangles, Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and astrocytosis in the cerebral cortex. The goal of this study is to investigate genetic factors associated with the neuronal proportion in health and disease. To identify cell-autonomous genetic variants associated with neuronal proportion in cortical tissues, we inferred cellular population structure from bulk RNA-Seq derived from 1536 individuals. We identified the variant rs1990621 located in the TMEM106B gene region as significantly associated with neuronal proportion (p value = 6.40 × 10^-07) and replicated this finding in an independent dataset (p value = 7.41 × 10^-04) surpassing the genome-wide threshold in the meta-analysis (p value = 9.42 × 10^-09). This variant is in high LD with the TMEM106B non-synonymous variant p.T185S (rs3173615; r² = 0.98) which was previously identified as a protective variant for frontotemporal lobar degeneration (FTLD). We stratified the samples by disease status, and discovered that this variant modulates neuronal proportion not only in AD cases, but also several neurodegenerative diseases and in elderly cognitively healthy controls. Furthermore, we did not find a significant association in younger controls or schizophrenia patients, suggesting that this variant might increase neuronal survival or confer resilience to the neurodegenerative process. The single variant and gene-based analyses also identified an overall genetic association between neuronal proportion, AD and FTLD risk. These results suggest that common pathways are implicated in these neurodegenerative diseases, that implicate neuronal survival. In summary, we identified a protective variant in the TMEM106B gene that may have a neuronal protection effect against general aging, independent of disease status, which could help elucidate the relationship between aging and neuronal survival in the presence or absence of neurodegenerative disorders. Our findings suggest that TMEM106B could be a potential target for neuronal protection therapies to ameliorate cognitive and functional deficits.

Keywords: Complex traits; Cortex; Deconvolution; GWAS; Neurodegeneration; QTL.

Figure 1.. Study Design.

RNA-Seq and paired genotype or whole genome sequencing (WGS) data were accessed and preprocessed for downstream analysis. Genotype data quality was ensured based on our quality control criteria and imputed as needed. WGS and imputed genotypes were merged, followed by principal component analysis (PCA) and identity by descent (IBD) to select unrelated subjects of European ancestry. RNA-Seq data quality was checked with FastQC and aligned to human GRCh37 primary assembly with STAR, from which transcript integrity number (TIN) was inferred with RSeQC to account for RNA integrity variation that we later incorporated into the analysis. Gene expression was quantified from unaligned RNA-Seq with the psuedo-aligner Salmon for deconvolution. Cell type composition comprised of the four major CNS cell types were inferred by performing deconvolution on gene expression quantification results. Using cell type proportions as quantitative traits, we identified loci in the TMEM106B gene region associated with neuronal proportion in our assembled dataset. CMC: CommonMind Consorsium; GTEx: The Genotype-Tissue Expression; Mayo: the Mayo Clinic; MSSM: Mount Sinai School of Medicine; Knight ADRC: the Charles F. and Joanne Knight Alzheimer’s Disease Research Center; DIAN: the Dominantly Inherited Alzheimer Network; ROSMAP: the Religious Orders Study and Memory and Aging Project; TCX: temporal cortex; PAR: parietal cortex; CTX: cortex; FCX: frontal cortex; DLPFC: dorsal lateral prefrontal cortex. BA9: dorsal lateral prefrontal cortex; BA10: Anterior prefrontal cortex; BA22: superior temporal gyrus; BA24: ventral anterior cingulate cortex; BA36: parahippocampal gyrus; BA44: inferior frontal gyrus.

Figure 2.. The single variant and gene-based multi-tissue meta-analyses identified TMEM106B and APOE as genes associated with neuronal proportion.

All panels in this figure were produced using meta-analysis results from Meta-Tissue analytic pipeline. a) Manhattan plot showing the SNP-based genome-wide significant hit located in chromosome 7 with other suggestive SNP hits labeled. rs1990621, located in the chromosome 7 TMEM106B gene region, was significantly associated with neuronal proportion in meta-analyses. b) QQ plot of the SNP-based analysis. c) Manhattan plot showing the gene- based genome-wide significant hit located in chromosome 7 with other suggestive genes. d) QQ plot of the gene-based analysis. e) Local plot showing the zoomed-in view of the hit in chromosome 7 with the target SNP rs1990622 labeled with dark purple. The top leading SNP is rs1990621. Nearby SNPs were also mainly located in the TMEM106B gene region and color coded with their linkage disequilibrium (LD) r2 thresholds. f) Local plot showing the zoomed-in view of the hit in chromosome 19 with the target SNP rs2075650 labeled with dark purple. The top three leading SNPs are rs283815, rs769449, and rs429358. Nearby SNPs were also mainly located in the TOMM40/APOE gene region and color coded with their LD r² thresholds. One gene omitted in this region is SNRPD2.

Figure 3.. Meta-Tissue analysis results of rs1990621.

a) Forest plot showing the p-value and confidence interval for rs1990621 for each tissue site of each dataset that is included in the Meta-Tissue meta-analysis. Summary random effects were depicted at the bottom as RE Summary. b) Based on Meta-Tissue meta-analysis, PM-Plot of rs1990621 is plotted while combining both p-value (y axis) and m-value (x axis). Red dots indicate that the variant is predicted to have an effect in that particular dataset, blue dots mean that the variant is predicted to not have an effect, and green dots represent ambiguous predictions. c) Forest plot p-value and confidence interval for rs1990621 for discovery, replication, and merged datasets. d) Forest plot p-value and confidence interval for rs1990621 when splitting the merged dataset into four main disease categories. CMC: CommonMind Consorsium; GTEx: The Genotype-Tissue Expression; Mayo: the Mayo Clinic; MSSM: Mount Sinai School of Medicine; Knight ADRC: the Charles F. and Joanne Knight Alzheimer’s Disease Research Center; DIAN: the Dominantly Inherited Alzheimer Network; ROSMAP: the Religious Orders Study and Memory and Aging Project; TCX: temporal cortex; PAR: parietal cortex; CTX: cortex; FCX: frontal cortex; DLPFC: dorsal lateral prefrontal cortex. BA9: dorsal lateral prefrontal cortex; BA10: Anterior prefrontal cortex; BA22: superior temporal gyrus; BA24: ventral anterior cingulate cortex; BA36: parahippocampal gyrus; BA44: inferior frontal gyrus; AD: Alzheimer’s Disease; SCZ: schizophrenia; Other: other non-AD neurodegenerative disorders.