Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein

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Abstract

To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS. We also observed multiple distinct protein-truncating variants in a highly constrained gene, DNAJC7. The signal in DNAJC7 exceeded genome-wide significance, and immunoblotting assays showed depletion of DNAJC7 protein in fibroblasts in a patient with ALS carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat-shock protein family, HSP40, which, along with HSP70 proteins, facilitates protein homeostasis, including folding of newly synthesized polypeptides and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of aberrant proteins can occur and lead to protein aggregation, which is a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.

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Fig. 1: Exome-wide enrichment of PTVs in ALS cases.
Fig. 2: Enrichment of PTVs in constrained genes in ALS cases.
Fig. 3: No enrichment of variants in known ALS genes, other related neurodegenerative disease genes or brain-specific genes.
Fig. 4: Quantile–quantile plot of discovery results for rare variants.
Fig. 5: Effects of DNAJC7 PTV p.Arg156Ter on transcript and protein levels.

Data availability

The sequencing data discussed in this publication were obtained through dbGaP and are available under the following accession codes: MIGen Exome Sequencing: Ottawa Heart (phs000806.v1.p1); MIGen Exome Sequencing: Leicester UK Heart Study (phs001000.v1.p1); Swedish Schizophrenia Population-Based Case-control Exome Sequencing (phs000473.v2.p2); Genome-Wide Association Study of Amyotrophic Lateral Sclerosis (phs000101.v5.p1).

Code availability

Code used to conduct the analysis is provided online (Supplementary Software).

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Acknowledgements

The authors thank and acknowledge the consent and cooperation of all study participants. Many thanks are given to F. Cerrato for helping assemble the dataset and providing general project management, and to T. Poterba, J. Bloom, D. King and C. Seed for their assistance in Hail. Data used in this research were in part obtained from the UK MND Collections for MND Research, funded by the MND Association and the Wellcome Trust. The authors thank people from MND and their families for their participation in this project. The project is supported through the following funding organizations under the aegis of the JPND (www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1)), the Economic and Social Research Council (ES/L008238/1)) and through the Motor Neurone Disease Association. This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. We acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. The CReATe consortium (U54NS092091) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. This consortium is funded through collaboration between NCATS and the NINDS. Additional support is provided by the ALS Association (17-LGCA-331). S.M.K.F. was supported by the ALS Canada Tim E. Noël Postdoctoral Fellowship. J.R.K. was supported by the Project ALS Tom Kirchhoff Family Postdoctoral Fellowship and acknowledges K. Mamia and L. T. Kane for their work banking fibroblasts.

Author information

S.M.K.F., M.J.D. and B.M.N. conceived and designed the experiments. S.M.K.F., S.D.T., H.P., B.N.S., E.R., G.W., J.W., A.S., A.I., A.A.K., D.A.M., S.G., K.E., R.R., J.L.M., R.S., S.Z., M.B., J.P.T., M.N., M.G., P.J.S., K.E.M., A.A.-C., B.T., C.E.S., D.B.G., M.B.H. and B.M.N. collected samples, prepared samples for analysis or were involved in clinical evaluation. M.B. and J.P.T. were the lead contacts for the CReATe Consortium. S.D.T. and C.E.S. were the lead contacts for the FALS Consortium. D.B.G. and M.B.H. were the lead contacts for the ALSGENS Consortium. S.M.K.F. performed all experiments and executed data analyses. D.P.H., L.E.A., A.E.B. and S.D.T. provided analysis suggestions. J.R.K. completed the cell culture, RNA and protein analyses. S.M.K.F. performed the primary writing of the manuscript with input from D.P.H., C.C., M.J.D. and B.M.N. All authors approved the final manuscript. M.J.D. and B.M.N. supervised the research.

Correspondence to Sali M. K. Farhan or Benjamin M. Neale.

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Competing interests

As a possible conflict of interest, M.N.’s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA. M.N. also consults for Lysosomal Therapeutics Inc, the Michael J. Fox Foundation and Vivid Genomics, among others. The other other authors declare no competing interests.

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Supplementary information

Supplementary Figure 1 Initial sample quality control analysis.

(A) Sample call rate. (B) Sample mean depth. (C) Sample mean genotype quality. (D) Sample transition to transversion ratio. (E) Sample heterozygous to homozygous ratio. (F) Sample insertion to deletion ratio. (G) Number of SNPs in each sample. (H) Number of singletons in each sample. N=3,864 ALS cases; N=7,839 controls. The box and whisker plots display the mean, minimum, and maximum.

Supplementary Figure 2 Principal component analysis of ALS dataset with 1000 Genomes.

(A) PC1 and PC2 of ALS dataset with 1000 Genomes. Cases, controls, and the European population is shown. N=3,864 ALS cases; N=7,839 controls. Each point represents one individual. (B) PC1 and PC3 of ALS dataset with 1000 Genomes. Cases, controls, and the European population is shown. (C) PC2 and PC3 of ALS dataset with 1000 Genomes. Cases, controls, and the European population is shown. (D) PC1 and PC2 of ALS dataset with 1000 Genomes. Cases, controls, and the European subpopulations are shown. (E) PC1 and PC3 of ALS dataset with 1000 Genomes. Cases, controls, and the European subpopulations are shown. (F) PC2 and PC3 of ALS dataset with 1000 Genomes. Cases, controls, and the European subpopulations are shown.

Supplementary Figure 3 All models together.

Model 1: Sample variation. The graph display the mean and standard deviation. P-values from firth logistic regression test are also displayed. Multiple test correction P-value: 0.0125. N=3,864 ALS cases; N=7,839 controls. Model 2: Sample variation, sample sex, PC1-PC10. Model 3: Sample variation, sample sex, PC1-PC10, and total exome count (summation of synonymous, benign missense, damaging missense, and PTV). Model 4: Sample variation, sample sex, PC1-PC10, and benign variation count (summation of synonymous and benign missense variation).

Supplementary Figure 4 Exome wide enrichment of SNV-based PTVs and indel-based PTVs in ALS cases.

Extension of Fig. 1: Evaluating the effects of SNV-based and indel-based PTVs within singletons (AC=1), doubletons (AC=2), ultra-rare singletons (AC=1, 0 in DiscovEHR), and rare variants (MAF<0.01 in our dataset, DiscovEHR and ExAC). Odds ratios and 95% confidence intervals for each class of variation are depicted by different colors. P-values are also displayed. Model 3 evaluates sample variation with the covariates, sample sex, PC1-10, and total exome count (summation of synonymous variation, benign missense variation, damaging missense variation, and PTV SNV or PTV indel). Model 4 evaluates sample variation with the covariates, sample sex, PC1-10, and benign variation (summation of synonymous and benign missense variation). The graph display the mean and standard deviation. P-values from firth logistic regression test are also displayed. Multiple test correction P-value: 0.0125. N=3,864 ALS cases; N=7,839 controls.

Supplementary Figure 5 Enrichment of variants in constrained genes in ALS cases.

Extension of Fig. 2a, b: (a) Evaluating the effects of constrained genes in synonymous variants, benign missense variants, damaging missense variants, and PTVs within singletons (AC=1), doubletons (AC=2), ultra-rare singletons (AC=1, 0 in DiscovEHR), and rare variants (MAF<0.01 in our dataset, DiscovEHR and ExAC). Odds ratios and 95% confidence intervals for each class of variation are depicted by different colors. P-values are also displayed. Model 3 evaluates sample variation with the covariates, sample sex, PC1-10, and total exome count (summation of synonymous variation, benign missense variation, damaging missense variation, and PTV). Model 4 evaluates sample variation with the covariates, sample sex, PC1-10, and benign variation (summation of synonymous and benign missense variation). (b) Evaluating the residual effects with constrained genes removed. The graph display the mean and standard deviation. P-values from firth logistic regression test are also displayed. Multiple test correction P-value: 0.0125. N=3,864 ALS cases; N=7,839 controls.

Supplementary Figure 6 Burden analysis of known ALS genes.

Extension of Fig. 3a: Evaluating the effects of known ALS genes in synonymous variants, benign missense variants, damaging missense variants, and PTVs within singletons (AC=1), doubletons (AC=2), ultra-rare singletons (AC=1, 0 in DiscovEHR), and rare variants (MAF<0.01 in our dataset, DiscovEHR and ExAC). Odds ratios and 95% confidence intervals for each class of variation are depicted by different colors. P-values are also displayed. Model 3 evaluates sample variation with the covariates, sample sex, PC1-10, and total exome count (summation of synonymous variation, benign missense variation, damaging missense variation, and PTV). Model 4 evaluates sample variation with the covariates, sample sex, PC1-10, and benign variation (summation of synonymous and benign missense variation). The graph display the mean and standard deviation. P-values from firth logistic regression test are also displayed. Multiple test correction P-value: 0.0125. N=3,864 ALS cases; N=7,839 controls.

Supplementary Figure 7 Analysis of other neurodegenerative disease genes.

Extension of Fig. 3b: Evaluating the effects of genes associated with other neurodegenerative disease (motor neuron diseases: primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, and spinal muscular atrophy; diseases with overlapping phenotypes: frontotemporal dementia, Parkinson’s disease, Pick’s disease, and Alzheimer’s disease) in synonymous variants, benign missense variants, damaging missense variants, and PTVs within singletons (AC=1), doubletons (AC=2), ultra-rare singletons (AC=1, 0 in DiscovEHR), and rare variants (MAF<0.01 in our dataset, DiscovEHR and ExAC). Odds ratios and 95% confidence intervals for each class of variation are depicted by different colors. P-values are also displayed. Model 3 evaluates sample variation with the covariates, sample sex, PC1-10, and total exome count (summation of synonymous variation, benign missense variation, damaging missense variation, and PTV). Model 4 evaluates sample variation with the covariates, sample sex, PC1-10, and benign variation (summation of synonymous and benign missense variation). The graph display the mean and standard deviation. P-values from firth logistic regression test are also displayed. Multiple test correction P-value: 0.0125. N=3,864 ALS cases; N=7,839 controls.

Supplementary Figure 8 Analysis of brain specific genes.

Extension of Fig. 3c: Analysis of brain specific genes in synonymous variants, benign missense variants, damaging missense variants, and PTVs within singletons (AC=1), doubletons (AC=2), ultra-rare singletons (AC=1, 0 in DiscovEHR), and rare variants (MAF<0.01 in our dataset, DiscovEHR and ExAC). Odds ratios and 95% confidence intervals for each class of variation are depicted by different colors. P-values are also displayed. Model 3 evaluates sample variation with the covariates, sample sex, PC1-10, and total exome count (summation of synonymous variation, benign missense variation, damaging missense variation, and PTV). Model 4 evaluates sample variation with the covariates, sample sex, PC1-10, and benign variation (summation of synonymous and benign missense variation). The graph display the mean and standard deviation. P-values from firth logistic regression test are also displayed. Multiple test correction P-value: 0.0125. N=3,864 ALS cases; N=7,839 controls.

Supplementary Figure 9 Quantile–quantile plots of ultra-rare singletons.

(a) Ultra-rare singletons (AC = 1, 0 in DiscovEHR database) for PTV. PTVs in NEK1 and OPTN, which are known ALS genes, are enriched in ALS cases. NEK1 and OPTN P values are displayed. (b) Ultra-rare singleton (AC = 1, 0 in DiscovEHR database) for damaging missense variants. Damaging missense variants in SOD1 are enriched in ALS cases. SOD1 P value is displayed.

Supplementary Figure 10 DNAJC7 qPCR and immunoblot assays.

(A-B) Relative levels of DNAJC7 mRNA in human fibroblasts using either primers recognizing exons 4 and 6 (A) or exons 13 and 14 (B). Levels for each sample were normalized to GAPDH and displayed relative to the average normalized levels of the healthy controls. Data are displayed as the mean of technical replicates with SD. (C) Uncropped immunoblot of human fibroblast protein lysates probed for the N-terminus of DNAJC7. Similar results were obtained in n=3 independent blots.

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Farhan, S.M.K., Howrigan, D.P., Abbott, L.E. et al. Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein. Nat Neurosci 22, 1966–1974 (2019) doi:10.1038/s41593-019-0530-0

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