Genome wide association study of clinical duration and age at onset of sporadic CJD DOI Open Access
Holger Hummerich,

Helen E. Speedy,

Tracy Campbell

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 17, 2023

Abstract Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research therapeutics. We assembled array genotyped sCJD cases diagnosed life autopsy. Clinical (median:4, interquartile range (IQR):2.5-9 (months)) was available 3,773 (median:67, IQR:61-73 (years)) 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved significance the duration; all which located chromosome 20 (top SNP rs1799990, pvalue=3.45×10 -36 , beta=0.34 an additive model; pvalue=9.92×10 -67 beta=0.84 a heterozygous model). Fine mapping, conditional expression suggests that well-known non-synonymous variant codon 129 obvious outstanding determinant duration. Pathway suggestive loci described. No significant found, but HS6ST3 gene (pvalue=1.93 × 10 -6 ) gene-based test. found no evidence genetic correlation between case-control (disease risk factors) case-only (determinants phenotypes) studies. Relative other variants, PRNP by far modifier CJD survival suggesting only modest rare effects loci.

Язык: Английский

Genome wide association study of clinical duration and age at onset of sporadic CJD DOI Open Access
Holger Hummerich,

Helen E. Speedy,

Tracy Campbell

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 17, 2023

Abstract Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research therapeutics. We assembled array genotyped sCJD cases diagnosed life autopsy. Clinical (median:4, interquartile range (IQR):2.5-9 (months)) was available 3,773 (median:67, IQR:61-73 (years)) 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved significance the duration; all which located chromosome 20 (top SNP rs1799990, pvalue=3.45×10 -36 , beta=0.34 an additive model; pvalue=9.92×10 -67 beta=0.84 a heterozygous model). Fine mapping, conditional expression suggests that well-known non-synonymous variant codon 129 obvious outstanding determinant duration. Pathway suggestive loci described. No significant found, but HS6ST3 gene (pvalue=1.93 × 10 -6 ) gene-based test. found no evidence genetic correlation between case-control (disease risk factors) case-only (determinants phenotypes) studies. Relative other variants, PRNP by far modifier CJD survival suggesting only modest rare effects loci.

Язык: Английский

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