Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum

International Frontotemporal Dementia (FTD)-Genomics Consortium, International Collaboration, Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium, International Parkinson's Disease Genomics Consortium

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)860-875
Number of pages16
JournalJAMA Neurology
Volume75
Issue number7
StatePublished - Jul 1 2018

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Amyotrophic Lateral Sclerosis
Progressive Supranuclear Palsy
Frontotemporal Dementia
Neurodegenerative Diseases
Genes
Motor Neurons
Frontotemporal Dementia With Motor Neuron Disease
Haplotypes
Parkinson Disease
Alzheimer Disease
Mitochondrial Degradation
Cytomegalovirus Infections
Brain
Spinal Cord
Consensus

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

International Frontotemporal Dementia (FTD)-Genomics Consortium, International Collaboration, Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium, & International Parkinson's Disease Genomics Consortium (2018). Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum. JAMA Neurology, 75(7), 860-875.

Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum. / International Frontotemporal Dementia (FTD)-Genomics Consortium, International Collaboration; Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium; International Parkinson's Disease Genomics Consortium.

In: JAMA Neurology, Vol. 75, No. 7, 01.07.2018, p. 860-875.

Research output: Contribution to journalArticle

International Frontotemporal Dementia (FTD)-Genomics Consortium, International Collaboration, Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium & International Parkinson's Disease Genomics Consortium 2018, 'Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum', JAMA Neurology, vol. 75, no. 7, pp. 860-875.
International Frontotemporal Dementia (FTD)-Genomics Consortium, International Collaboration, Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium, International Parkinson's Disease Genomics Consortium. Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum. JAMA Neurology. 2018 Jul 1;75(7):860-875.
International Frontotemporal Dementia (FTD)-Genomics Consortium, International Collaboration ; Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium ; International Parkinson's Disease Genomics Consortium. / Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum. In: JAMA Neurology. 2018 ; Vol. 75, No. 7. pp. 860-875.
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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.",
author = "{International Frontotemporal Dementia (FTD)-Genomics Consortium, International Collaboration} and {Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium} and {International Parkinson's Disease Genomics Consortium} and Karch, {Celeste M.} and Natalie Wen and Fan, {Chun C.} and Yokoyama, {Jennifer S.} and Naomi Kouri and Ross, {Owen A} and Gunter H{\"o}glinger and Ulrich M{\"u}ller and Raffaele Ferrari and John Hardy and Schellenberg, {Gerard D.} and Sleiman, {Patrick M.} and Parastoo Momeni and Hess, {Christopher P.} and Miller, {Bruce L.} and Manu Sharma and {Van Deerlin}, Vivianna and Smeland, {Olav B.} and Andreassen, {Ole A.} and Dale, {Anders M.} and Desikan, {Rahul S.}",
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T1 - Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum

AU - International Frontotemporal Dementia (FTD)-Genomics Consortium, International Collaboration

AU - Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium

AU - International Parkinson's Disease Genomics Consortium

AU - Karch, Celeste M.

AU - Wen, Natalie

AU - Fan, Chun C.

AU - Yokoyama, Jennifer S.

AU - Kouri, Naomi

AU - Ross, Owen A

AU - Höglinger, Gunter

AU - Müller, Ulrich

AU - Ferrari, Raffaele

AU - Hardy, John

AU - Schellenberg, Gerard D.

AU - Sleiman, Patrick M.

AU - Momeni, Parastoo

AU - Hess, Christopher P.

AU - Miller, Bruce L.

AU - Sharma, Manu

AU - Van Deerlin, Vivianna

AU - Smeland, Olav B.

AU - Andreassen, Ole A.

AU - Dale, Anders M.

AU - Desikan, Rahul S.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

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