Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study.
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Jones Emma, Hummerich Holger, Viré Emmanuelle, Uphill James, Dimitriadis Athanasios, Speedy Helen, Campbell Tracy, Norsworthy Penny, Quinn Liam, Whitfield Jerome, Linehan Jacqueline, Jaunmuktane Zane, Brandner Sebastian, Jat Parmjit, Nihat Akin, How Mok Tze, Ahmed Parvin, Collins Steven, Stehmann Christiane, Sarros Shannon, Kovacs Gabor G, Geschwind Michael D, Golubjatnikov Aili, Frontzek Karl, Budka Herbert, Aguzzi Adriano, Karamujić-Čomić Hata, van der Lee Sven J, Ibrahim-Verbaas Carla A, van Duijn Cornelia M, Sikorska Beata, Golanska Ewa, Liberski Pawel P, Calero Miguel, Calero Olga, Sanchez-Juan Pascual, Salas Antonio, Martinón-Torres Federico, Bouaziz-Amar Elodie, Haïk Stéphane, Laplanche Jean-Louis, Brandel Jean-Phillipe, Amouyel Phillipe, Lambert Jean-Charles, Parchi Piero, Bartoletti-Stella Anna, Capellari Sabina, Poleggi Anna, Ladogana Anna, Pocchiari Maurizio, Aneli Serena, Matullo Giuseppe, Knight Richard, Zafar Saima, Zerr Inga, Booth Stephanie, Coulthart Michael B, Jansen Gerard H, Glisic Katie, Blevins Janis, Gambetti Pierluigi, Safar Jiri, Appleby Brian, Collinge John, Mead Simon
Аннотация
METHODS: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country.
FINDINGS: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10-15; heterozygous model p=1·01 × 10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions.
INTERPRETATION: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders.
FUNDING: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.