Table 6 Annotated metabolites with mQTL results, phenotypic traits and literature findings.

N-Desmethyl O-desacetyl diltiazem glucuronide

N-Desmethyl O-desacetyl hydroxy diltiazem glucuronide

1

Regulatory feature: ENSR00000006069

Anxiety and major depressive disorder, Obesity-related traits

N-Desmethyl hydroxy diltiazem glucuronide

15

MESP2

Coronary artery aneurysm in Kawasaki disease

Paracetamol

Paracetamol sulphate

3-Methoxy-paracetamol sulphate

4 AND 17

SORCS2 AND CNTROB

Biopolar disorder, Interleukin-10 levels

SORCS2 belongs to the Vps10 receptor family that has previously been linked to neurodegeneration and AD^33,34,35, and is known to play functional roles in protein transport. In addition, the receptor family includes the SORL1 gene that encodes protein SorLA—a key protein in amyloid-beta precursor protein (APP) processing³⁶.

Quinine

2

AOX1

Late-onset Alzheimer’s disease

The mQTL association links aldehyde oxydase 1 (AOX1) gene and quinine. AOX1 gene has a previously reported GWAS trait “Late-onset Alzheimer’s disease”³⁷.

Cholesterol metabolism (CM)

Hydroxylated pregnenolone sulphate N-acetylglucosamine isomer 2*

7

CHN2

Age at onset, Alzheimer’s disease, Obesity-related traits, Psychosis

Beta-chimaerin (CHN2) gene plays a role in neural development by regulating Rac1 activity³⁸ and is known to be downregulated with age. Through Rac1 activation, gene CHN2 is linked with Alzheimer’s disease³⁹.

Hydroxylated pregnenolone sulphate N-acetylglucosamine isomer 1*

Pregnenolone sulphate N-acetylglucosamine

Pregnanediol sulphate N-acetylglucosamine

Tauro(cheno) deoxycholic acid N-acetylglucosaminide *

5

UGT3A1

Blood metabolite levels, Primary biliary cholangitis (PBC)

Neither the gene UGT3A1 nor the PBC has a known relationship to AD, although we note that a progressive cognitive impairment different to delirium is a feature of PBC, independently of liver pathology^40,41. In animal models of biliary cirrhosis that has led to memory impairment, hippocampal pregnenolone sulphate infusion resulted in a memory-enhancing effect⁴².

CM, gut microbiota

3-Aminoisobutyrate

5

AGXT2

Metabolite levels, Asymmetrical dimethylarginine levels, Symmetrical dimethylarginine levels

Gut microbiota

N,N,N-Trimethyl-l-alanyl-l-proline betaine

11 AND 21

Regulatory feature: ENSR00000961656 AND intergenic variant

Butyryl or isobutyryl carnitine *

15

intergenic variant

Trimethylamine

10

PYROXD2

General cognitive ability, Obesity-related traits, Metabolite levels

l-Lysine

19

SLC7A9

Estimated glomerular filtration rate, Creatinine levels

DNA methylation

5-Methylcytidine

4

CC2D2, FBXL5, FAM200B, BST1

Parkinson’s disease, Blood protein levels, Cerebrospinal fluid biomarker levels

The FBXL5 gene is a critical component of iron metabolism⁴³. It is associated with Parkinson’s disease (PD) in a region of chromosome 4. Iron dysregulation has long been associated with both PD and AD⁴⁴.

2-O-methylcytidine

9

NUP188, DOLK, PHYHD1, SH3GLB2

Body mass index

The PHYHD1 gene encodes 2-oxoglutarate oxygensase, an amyloid-beta interacting protein that has been shown to be dysregulated in both AD brain and in transgenic models with plaque pathology^45,46.

Unknown nucleoside with adenosyl moiety

12

Intergenic variant

The nearest gene to mQTL region is SYT1. It encodes protein synaptotagmin—a novel cerebrospinal fluid biomarker for Alzheimer’s disease⁴⁷.

Polyamine metabolism

N- Acetylisoputreanine-gamma-lactam

2

Long intergenic non-protein coding RNA LINC01914

CM, insulin resistance

Sucrose

8

Intergenic variant

Galactose

19

FUT2

Estimated glomerular filtration rate, Cholesterol levels