Additional file 1 of Triangulating evidence from observational and Mendelian randomization studies of ketone bodies for cognitive performance
Creators: name: Sae-jie, Wichanon
name: Supasai, Suangsuda
name: Kivimaki, Mika
name: Price, Jackie F.
name: Wong, Andrew
name: Kumari, Meena
name: Engmann, Jorgen
name: Shah, Tina
name: Schmidt, Amand F.
name: Gaunt, Tom R.
name: Hingorani, Aroon
name: Charoen, Pimphen
Publisher: name: figshare
Year: 2023
Subjects: Medicine
Neuroscience
Biotechnology
Mental Health

description: Additional file 1: Appendix S1. List of additional UCLEB members. Supplementary Methods. Fig. S1. Hypothesized biological pathway linking ketone body metabolism and cognitive functions. During fasting, fatty acids are converted into acetoacetate (ACACE) and 3-β-hydroxybutyrate (BOHBUT) through Acetyl CoA. BOHBUT and ACACE cross the blood-brain barrier (BBB) and enter neurons through a monocarboxylate transporter (MCT) channel. Once BOHBUT and ACACE enter the brain, a series of reactions occur to form Acetyl CoA. These reactions involve the 3-oxoacid CoA-transferase 1 (OXCT1) enzyme which is encoded by the OXCT1 gene. The product of OXCT1 is then converted to acetyl-CoA and subsequently enters the tricarboxylic acid (TCA) cycle for oxidation and ATP production [5]. BOHBUT and ACACE have been suggested to contribute to the secretion of Brain-derived neurotrophic factor (BDNF). This protein molecule is involved in the enhancement of mitochondrial biogenesis and synaptic plasticity, a key to learning ability and memory [6,7]. Table S1. Details of studies and datasets included in analyses. Table S2.Baseline characteristics of participants in the WHII study. Table S3. Multiple linear regression examining the association between BOHBUT and ACACE as a continuous variable and cognitive function scores. The models were adjusted by age, sex, diabetes (yes/no), smoking (ever/never), alcohol consumption (heavy/other), waist-to-hip ratio, and socioeconomic status (low/intermediate/high). Table S4. SNPs associated with ACACE using clumping windows -/+ 10 000 kb and r2 &lt; 0.001. Table S5. SNPs associated with BOHBUT using clumping window -/+ 10 000 kb and r2&lt; 0.001. Table S6. SNPs associated with ACACE using clumping window -/+ 10 000 kb and r2&lt; 0.001. Table S7. Association analyses between 3-β-hydroxybutyrate instrumental SNPs and potential confounders, including alcohol (ever/never), diabetes (yes/no), adiposity, i.e., waist-to-hip ratio, and occupational position (low/intermediate/high). Table S8. Association analyses between acetoacetate instrumental SNPs and potential confounders, including alcohol (ever/never), diabetes (yes/no), adiposity, i.e., waist-to-hip ratio, and occupational position (low/intermediate/high). Table S9. MR of BOHBUT on cognitive performance and Alzheimer’s disease using 5 instrumental SNPs associated with BOHBUT (GWAS threshold: P&lt; 5 × 10-8). Table S10. MR of BOHBUT on cognitive performance and Alzheimer’s disease using 19 instrumental SNPs associated with BOHBUT (GWAS threshold: P &lt; 1 × 10-5).Table S11. Heterogeneity and pleiotropy tests in MR of BOHBUT on cognitive performance and Alzheimer’s disease. Table S12. MR of ACACE on cognitive performance and Alzheimer’s disease using 3 instrumental SNPs associated with ACACE (GWAS threshold: P &lt; 5 × 10-8). Table S13. MR of ACACE on cognitive performance and Alzheimer’s disease using 14 instrumental SNPs associated with ACACE (GWAS threshold: P &lt; 1 × 10-5). Table S14. Heterogeneity and pleiotropy tests in MR of ACACE on cognitive performance and Alzheimer’s disease. Table S15. MR of BOHBUT on cognitive performance and Alzheimer’s disease using 4 instrumental SNPs (rs6982503 was removed) associated with BOHBUT (GWAS threshold: P &lt; 5 × 10-8). Table S16. cis-SNPs in OXCT1 (GWAS threshold: P &lt; 1 × 10-5) using clumping window -/+ 10 000 kb and LD-r2 &lt; 0.4. Table S17. cis-MR for a causal estimate of OXCT1 locus on cognitive performance and Alzheimer’s disease.