TY - JOUR

T1 - Cerebrospinal Fluid C1-Esterase Inhibitor and Tie-1 Levels Affect Cognitive Performance

T2 - Evidence from Proteome-Wide Mendelian Randomization

AU - Zagkos, Loukas

AU - Dib, Marie Joe

AU - Cronjé, Héléne T.

AU - Elliott, Paul

AU - Dehghan, Abbas

AU - Tzoulaki, Ioanna

AU - Gill, Dipender

AU - Daghlas, Iyas

N1 - Publisher Copyright: © 2024 by the authors.

PY - 2024

Y1 - 2024

N2 - Objective: The association of cerebrospinal fluid (CSF) protein levels with cognitive function in the general population remains largely unexplored. We performed Mendelian randomization (MR) analyses to query which CSF proteins may have potential causal effects on cognitive performance. Methods and analysis: Genetic associations with CSF proteins were obtained from a genome-wide association study conducted in up to 835 European-ancestry individuals and for cognitive performance from a meta-analysis of GWAS including 257,841 European-ancestry individuals. We performed Mendelian randomization (MR) analyses to test the effect of randomly allocated variation in 154 genetically predicted CSF protein levels on cognitive performance. Findings were validated by performing colocalization analyses and considering cognition-related phenotypes. Results: Genetically predicted C1-esterase inhibitor levels in the CSF were associated with a better cognitive performance (SD units of cognitive performance per 1 log-relative fluorescence unit (RFU): 0.23, 95% confidence interval: 0.12 to 0.35, p = 7.91 × 10−5), while tyrosine-protein kinase receptor Tie-1 (sTie-1) levels were associated with a worse cognitive performance (−0.43, −0.62 to −0.23, p = 2.08 × 10−5). These findings were supported by colocalization analyses and by concordant effects on distinct cognition-related and brain-volume measures. Conclusions: Human genetics supports a role for the C1-esterase inhibitor and sTie-1 in cognitive performance.

AB - Objective: The association of cerebrospinal fluid (CSF) protein levels with cognitive function in the general population remains largely unexplored. We performed Mendelian randomization (MR) analyses to query which CSF proteins may have potential causal effects on cognitive performance. Methods and analysis: Genetic associations with CSF proteins were obtained from a genome-wide association study conducted in up to 835 European-ancestry individuals and for cognitive performance from a meta-analysis of GWAS including 257,841 European-ancestry individuals. We performed Mendelian randomization (MR) analyses to test the effect of randomly allocated variation in 154 genetically predicted CSF protein levels on cognitive performance. Findings were validated by performing colocalization analyses and considering cognition-related phenotypes. Results: Genetically predicted C1-esterase inhibitor levels in the CSF were associated with a better cognitive performance (SD units of cognitive performance per 1 log-relative fluorescence unit (RFU): 0.23, 95% confidence interval: 0.12 to 0.35, p = 7.91 × 10−5), while tyrosine-protein kinase receptor Tie-1 (sTie-1) levels were associated with a worse cognitive performance (−0.43, −0.62 to −0.23, p = 2.08 × 10−5). These findings were supported by colocalization analyses and by concordant effects on distinct cognition-related and brain-volume measures. Conclusions: Human genetics supports a role for the C1-esterase inhibitor and sTie-1 in cognitive performance.

KW - cognition

KW - CSF

KW - SERPING1

KW - TIE1

KW - tyrosine-protein kinase receptor

U2 - 10.3390/genes15010071

DO - 10.3390/genes15010071

M3 - Journal article

C2 - 38254961

AN - SCOPUS:85183175589

VL - 15

JO - Genes

JF - Genes

SN - 2073-4425

IS - 1

M1 - 71

ER -