Preprint
Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects
bioRxiv
Cold Spring Harbor laboratory
06/18/2024
DOI: 10.1101/2024.06.10.597797
PMCID: PMC11212857
PMID: 38948755
Abstract
Huntington's disease (HD), due to expansion of a CAG repeat in HTT , is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5'-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.Huntington's disease (HD), due to expansion of a CAG repeat in HTT , is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5'-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.
Details
- Title: Subtitle
- Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects
- Creators
- Jong-Min LeeZachariah L McLeanKevin CorreiaJun Wan ShinSujin LeeJae-Hyun JangYukyeong LeeKyung-Hee KimDoo Eun ChoiJeffrey D LongDiane LucenteIhn Sik SeongRicardo Mouro PintoJames V GiordanoJayalakshmi S MysoreJacqueline SicilianoEmanuela EleziJayla RulieraTammy GillisVanessa C WheelerMarcy E MacDonaldJames F GusellaAnna GatsevaMarc CiosiVilija LomeikaiteHossameldin LoayDarren G MoncktonChristopher WillsThomas H MasseyLesley JonesPeter HolmansSeung KwakCristina SampaioMichael OrthG Bernhard LandwehrmeyerJane S PaulsenE Ray DorseyRichard H Myers
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- Publisher
- Cold Spring Harbor laboratory
- DOI
- 10.1101/2024.06.10.597797
- PMID
- 38948755
- PMCID
- PMC11212857
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Language
- English
- Date posted
- 06/18/2024
- Academic Unit
- Psychiatry; Biostatistics
- Record Identifier
- 9984649959102771
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