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All Publications

  • Rare variant and polygenic analyses of amyotrophic lateral sclerosis in the French-Canadian genome. Genetics in medicine : official journal of the American College of Medical Genetics Ross, J. P., Akcimen, F., Liao, C., Kwan, K., Phillips, D. E., Schmilovich, Z., Spiegelman, D., Genge, A., Dupre, N., Dion, P. A., Farhan, S. M., Rouleau, G. A. 2023: 100967


    PURPOSE: The genetic etiology of amyotrophic lateral sclerosis (ALS) includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both.METHODS: 335 ALS cases and 356 controls from Quebec, Canada were concurrently tested by SNP-chip genotyping and targeted sequencing of ALS genes known at the time of study inception. ALS GWAS summary statistics were used to estimate an ALS polygenic risk score (PRS). Cases and controls were subdivided into rare variant heterozygotes and non-heterozygotes.RESULTS: Risk for ALS was significantly associated with PRS and rare variants independently in a logistic regression model. While ALS PRS predicted a small amount of ALS risk overall, the effect was most pronounced between ALS cases and controls that were not heterozygous for a rare variant in the ALS genes surveyed.CONCLUSION: Both PRS and rare variants in ALS genes impact risk for ALS. PRS for ALS is most informative when rare variants are not observed in ALS genes.

    View details for DOI 10.1016/j.gim.2023.100967

    View details for PubMedID 37638500

  • Evolution of a Human-Specific Tandem Repeat Associated with ALS. American journal of human genetics Course, M. M., Gudsnuk, K. n., Smukowski, S. N., Winston, K. n., Desai, N. n., Ross, J. P., Sulovari, A. n., Bourassa, C. V., Spiegelman, D. n., Couthouis, J. n., Yu, C. E., Tsuang, D. W., Jayadev, S. n., Kay, M. A., Gitler, A. D., Dupre, N. n., Eichler, E. E., Dion, P. A., Rouleau, G. A., Valdmanis, P. N. 2020


    Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3'-5' direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.

    View details for DOI 10.1016/j.ajhg.2020.07.004

    View details for PubMedID 32750315