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  • Neumann, Alexander (author)

Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/333006
  • https://gup.ub.gu.se/publication/333006URI
  • https://doi.org/10.1186/s13073-023-01233-zDOI

Supplementary language notes

  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n=205 controls, n=546 mild cognitive impairment, n=222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analysesof the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

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  • Ohlei, Olena (author)
  • Küçükali, Fahri (author)
  • Bos, Isabelle J (author)
  • Timsina, Jigyasha (author)
  • Vos, Stephanie (author)
  • Prokopenko, Dmitry (author)
  • Tijms, Betty M (author)
  • Andreasson, Ulf,1968Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xaulfz (author)
  • Blennow, Kaj,1958Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xbleka (author)
  • Vandenberghe, Rik (author)
  • Scheltens, Philip (author)
  • Teunissen, Charlotte E (author)
  • Engelborghs, Sebastiaan (author)
  • Frisoni, Giovanni B (author)
  • Blin, Oliver (author)
  • Richardson, Jill C (author)
  • Bordet, Régis (author)
  • Lleó, Alberto (author)
  • Alcolea, Daniel (author)
  • Popp, Julius (author)
  • Marsh, Thomas W (author)
  • Gorijala, Priyanka (author)
  • Clark, Christopher (author)
  • Peyratout, Gwendoline (author)
  • Martinez-Lage, Pablo (author)
  • Tainta, Mikel (author)
  • Dobson, Richard J B (author)
  • Legido-Quigley, Cristina (author)
  • Van Broeckhoven, Christine (author)
  • Tanzi, Rudolph E (author)
  • Ten Kate, Mara (author)
  • Lill, Christina M (author)
  • Barkhof, Frederik (author)
  • Cruchaga, Carlos (author)
  • Lovestone, Simon (author)
  • Streffer, Johannes (author)
  • Zetterberg, Henrik,1973Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xzethe (author)
  • Visser, Pieter Jelle (author)
  • Sleegers, Kristel (author)
  • Bertram, Lars (author)
  • Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi (creator_code:org_t)

Related titles

  • In:Genome medicine15:11756-994X

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