MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
Authors: Flower Michael , Lomeikaite Vilija , Ciosi Marc , Cumming Sarah , Morales Fernando , Lo Kitty , Hensman Moss Davina , Jones Lesley , Holmans Peter , Monckton Darren G , Tabrizi Sarah J ,   TRACK-HD Investigators, Kraus Peter , Hoffman Rainer , Tobin Alan , Borowsky Beth , Keenan S , Whitlock Kathryn B , Queller Sarah , Campbell Colin , Wang Chiachi , Langbehn Doug , Axelson Eric , Johnson Hans , Acharya Tanka , Cash Dave M , Frost Chris , Jones Rebecca , Jurgens Caroline , ‘t Hart Ellen P , van der Grond Jeroen , Witjes- Ane Marie-Noelle N , Roos Raymund A C , Dumas Eve M , van den Bogaard Simon J A , Stopford Cheryl , Craufurd David , Callaghan Jenny , Arran Natalie , Rosas Diana D , Lee S , Monaco W , O’Regan Alison , Milchman Cassie , Frajman E , Labuschagne Izelle , Stout Julie , Campbell Melissa , Andrews Sophie C , Bechtel Natalie , Reilmann Ralf , Bohlen Stefan , Kennard Chris , Berna Claire , Hicks Stephen , Durr Alexandra , Pourchot C , Bardinet Eric , Nigaud Kevin , Valabre Romain , gue ` , Lehericy Stephane , Marelli Cecilia , Jauffret Celine , Justo Damian , Leavitt Blair , Decolongon Joji , Sturrock Aaron , Coleman Alison , Santos Rachelle Dar , Patel A , Gibbard Claire , Whitehead Daisy , Wild Ed , Owen Gail , Crawford Helen , Malone Ian , Lahiri Nayana , Fox Nick C , Hobbs Nicola Z , Scahill Rachael I , Ordidge Roger , Pepple Tracey , Read Joy , Say Miranda J , Landwehrmeyer Bernhard ,   OPTIMISTIC Consortium, Daidj Ferroudja , Bassez Guillaume , Lignier Baptiste , Couppey Florence , Delmas Stéphanie , Deux Jean-François , Hankiewicz Karolina , Dogan Celine , Minier Lisa , Chevalier Pascale , Hamadouche Amira , Catt Michael , van Hees Vincent , Catt Sharon , Schwalber Ameli , Dittrich Juliane , Kierkegaard Marie , Wenninger Stephan , Schoser Benedikt , Schüller Angela , Stahl Kristina , Künzel Heike , Wolff Martin , Jellinek Anna , Moreno Cecilia Jimenez , Gorman Grainne , Lochmüller Hanns , Trenell Michael , van Laar Sandra , Wood Libby , Cassidy Sophie , Newman Jane , Charman Sarah , Steffaneti Renae , Taylor Louise , Brownrigg Allan , Day Sharon , Atalaia Antonio , Raaphorst Joost , Okkersen Kees , van Engelen Baziel , Nikolaus Stephanie , Cornelissen Yvonne , van Nimwegen Marlies , Maas Daphne , Klerks Ellen , Bouman Sacha , Knoop Hans , Heskamp Linda , Heerschap Arend , Rahmadi Ridho , Groot Perry , Heskes Tom , Kapusta Katarzyna , Glennon Jeffrey , Abghari Shaghayegh , Aschrafi Armaz , Poelmans Geert , Treweek Shaun , Hogarth Fiona , Littleford Roberta , Donnan Peter , Hapca Adrian , Hannah Michael , McKenzie Emma , Rauchhaus Petra , Cumming Sarah A , Monckton Darren G , Adam Berit , Faber Catharina , Merkies Ingemar 
Published: April 2019

The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.