Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

Abstract

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood.

Objectives: To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways.

Design, setting, and participants: In this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria.

Main outcomes and measures: The primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models.

Results: Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002) and in brains of patients with PSP (80 controls: 39 females; mean age, 82 years, mean [SE] value, 6.8 [0.2] AU; 84 patients with PSP: 33 females, mean age 74 years, mean [SE] value, 6.8 [0.1] AU; β = -0.19; P = .009) or FTD (11 controls: 4 females; mean age, 67 years; mean [SE] value, 6.74 [0.05] AU; 17 patients with FTD: 10 females; mean age, 69 years; mean [SE] value, 6.53 [0.04] AU; P = .005).

Conclusions and relevance: This study found novel genetic overlap between ALS and diseases of the FTD spectrum, that the MAPT H1 haplotype confers risk for ALS, and identified the mitophagy-associated, proapoptotic protein BNIP1 as an ALS risk gene. Together, these findings suggest that sporadic ALS may represent a selectively pleiotropic, polygenic disorder.

Figure 1.. Genetic Enrichment Across the Amyotrophic Lateral Sclerosis (ALS)–Frontotemporal Dementia (FTD) Spectrum

A, Fold-enrichment plots. Graphs depict enrichment vs nominal −log₁₀ P values (corrected for inflation) in amyotrophic lateral sclerosis (ALS) below the standard genome-wide association study threshold of P < 5 × 10⁻⁸ as a function of significance of association with Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) (sporadic and FTD with TDP-43 inclusions [TDP43]) and at the level of −log₁₀ P ≥ 0 corresponding to −log₁₀ P ≤ 1, −log₁₀ P ≥ 1 corresponding to P ≤ .10, and –log₁₀ P ≥ 2 corresponding to P ≤ .01. B, Conjunction Manhattan plot showing shared risk loci. A plot of conjunction −log₁₀ (false discovery rate [FDR]) values for ALS given PSP, CBD, TDP-43, and FTD. Single-nucleotide polymorphisms (SNPs) with conjunction −log₁₀ FDR > 1.3 (ie, FDR P < .05) are shown as large points. A black line around the large points indicates the most significant SNP in each linkage disequilibrium block. This SNP was annotated with the nearest gene, which is listed above the symbols in each locus.

Figure 2.. Reduced BNIP1 Expression in Neurodegenerative Tissue

A, Differential expression in motor neurons isolated from patients with amyotrophic lateral sclerosis (ALS) (GSE833 [Gene Expression Omnibus accession number]; mean [SEM] value, 3984 [760.8] arbitrary units [AU] for 4 controls and 1999 [274.1] AU for 7 patients with ALS; P = .02). B, Differential expression in homogenates from brains of patients with frontotemporal dementia (FTD) (GSE13162; mean [SEM] value, 6.7 [0.05] AU for 11 controls and 6.5 [0.04] AU for 17 patients with FTD; P = .005). C, Differential expression in homogenates from brains of patients with progressive supranuclear palsy (PSP) (syn6090802; mean [SEM] value, 6.8 [0.2] AU for 80 controls and 6.8 [0.1] AU for 84 patients with PSP; P = .009). D, Differential expression in homogenates from spinal cords of SOD1 WT and SOD1 G93A transgenic mice (GSE4390; mean [SEM] value, 13.8 [0.09] AU for 2 SOD1 WT mice and 11.5 [0.025] AU for 2 SOD1 G93A mice; P = .002).