A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis

Majid Pahlevan Kakhki, Antonino Giordano, Chiara Starvaggi Cucuzza, Tejaswi Venkata S. Badam, Samudyata Samudyata, Marianne Victoria Lemée, Pernilla Stridh, Asimenia Gkogka, Klementy Shchetynsky, Adil Harroud, Alexandra Gyllenberg, Yun Liu, Sanjaykumar Boddul, Tojo James, Melissa Sorosina, Massimo Filippi, Federica Esposito, Fredrik Wermeling, Mika Gustafsson, Patrizia Casaccia, Jan Hillert, Tomas Olsson, Ingrid Kockum, Carl M. Sellgren, Christelle Golzio, Lara Kular () and Maja Jagodic ()
Additional contact information
Majid Pahlevan Kakhki: Karolinska University Hospital
Antonino Giordano: Karolinska University Hospital
Chiara Starvaggi Cucuzza: Karolinska University Hospital
Tejaswi Venkata S. Badam: Karolinska University Hospital
Samudyata Samudyata: Karolinska Institutet
Marianne Victoria Lemée: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Pernilla Stridh: Karolinska University Hospital
Asimenia Gkogka: Karolinska Institutet
Klementy Shchetynsky: Karolinska University Hospital
Adil Harroud: The Neuro (Montreal Neurological Institute-Hospital)
Alexandra Gyllenberg: Karolinska University Hospital
Yun Liu: Fudan University
Sanjaykumar Boddul: Karolinska University Hospital
Tojo James: Karolinska University Hospital
Melissa Sorosina: IRCCS San Raffaele Scientific Institute
Massimo Filippi: IRCCS San Raffaele Hospital
Federica Esposito: IRCCS San Raffaele Hospital
Fredrik Wermeling: Karolinska University Hospital
Mika Gustafsson: Linköping university
Patrizia Casaccia: Icahn School of Medicine at Mount Sinai
Jan Hillert: Karolinska University Hospital
Tomas Olsson: Karolinska University Hospital
Ingrid Kockum: Karolinska University Hospital
Carl M. Sellgren: Karolinska Institutet
Christelle Golzio: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Lara Kular: Karolinska University Hospital
Maja Jagodic: Karolinska University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Multiple Sclerosis (MS) is a heterogeneous inflammatory and neurodegenerative disease with an unpredictable course towards progressive disability. Treating progressive MS is challenging due to limited insights into the underlying mechanisms. We examined the molecular changes associated with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. In PPMS, we found hypermethylation of the 1q21.1 locus, controlled by PPMS-specific genetic variations and influencing the expression of proximal genes (CHD1L, PRKAB2) in the brain. Evidence from reporter assay and CRISPR/dCas9 experiments supports a causal link between methylation and expression and correlation network analysis further implicates these genes in PPMS brain processes. Knock-down of CHD1L in human iPSC-derived neurons and knock-out of chd1l in zebrafish led to developmental and functional deficits of neurons. Thus, several lines of evidence suggest a distinct genetic-epigenetic-transcriptional interplay in the 1q21.1 locus potentially contributing to PPMS pathogenesis.

Date: 2024
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DOI: 10.1038/s41467-024-50794-z

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