Des-Arg(9) bradykinin as a causal metabolite for autism spectrum disorder

Table 1 Details of the genome-wide association studies consortiums

Variable	Ancestry	Ref.	Sample size	Sex	Data download
Metabolite	European	Shin et al[20], 2014	7824	Mixed	http://metabolomics.helmholtz-muenchen.de/gwas/
Autism spectrum disorder	European	Grove et al[21], 2017	Cases = 18381; Controls = 27969	Mixed	https://doi.org/10.6084/m9.figshare.14671989

Table 2 Nominally significant results of the inverse variance weighted method

ID	Metabolite	Outcome	SNP, n	β	SE	P value
M02137	Biliverdin	ASD	3	-0.255	0.122	0.038
M20675	1,5-Anhydroglucitol	ASD	5	-0.881	0.407	0.031
M32412	Butyrylcarnitine	ASD	12	-0.219	0.111	0.049
M32497	10-undecenoate (11:1n1)	ASD	3	0.546	0.258	0.034
M32847	X-11530	ASD	3	-0.302	0.125	0.016
M33137	X-11792	ASD	3	0.388	0.093	3.03 × 10-5
M33138	Oxidized bilirubin	ASD	3	-0.318	0.148	0.032
M34306	X-12696	ASD	4	-0.831	0.325	0.011
M34407	Isovalerylcarnitine	ASD	4	-0.976	0.393	0.013
M34420	Des-Arg(9) bradykinin	ASD	3	0.262	0.064	4.64 × 10-5
M36131	Alpha-glutamyltyrosine	ASD	3	-0.619	0.213	0.004

ASD: Autism spectrum disorder; SNP: Single nucleotide polymorphism.

Table 3 Heterogeneity and pleiotropy tests of the 8 metabolites

Metabolite	Heterogeneity, MR Egger P value	Heterogeneity, IVW P value	Pleiotropy, P value
Biliverdin	0.392	0.415	0.496
1,5-anhydroglucitol	0.482	0.034	0.067
Butyrylcarnitine	0.174	0.007	0.016
10-Undecenoate (11:1n1)	0.844	0.689	0.556
Oxidized bilirubin	0.271	0.385	0.586
Isovalerylcarnitine	0.030	0.058	0.744
Des-Arg(9) bradykinin	0.663	0.906	0.949
Alpha-glutamyltyrosine	0.785	0.923	0.817

MR: Mendelian randomization; IVW: Inverse variant weight.

Table 4 Top 10 predicted targets of Des-Arg(9)-bradykinin in SwissTargetPrediction

Target	Common name	Target class	Probability
Bradykinin B1 receptor	BDKRB1	Family A G protein-coupled receptor	0.420
Neurotensin receptor 1	NTSR1	Family A G protein-coupled receptor	0.189
Thrombin	F2	Protease	0.169
HLA class I histocompatibility antigen A-3	HLA-A	Surface antigen	0.140
Mu opioid receptor	OPRM1	Family A G protein-coupled receptor	0.131
Delta opioid receptor	OPRD1	Family A G protein-coupled receptor	0.131
Kappa opioid receptor	OPRK1	Family A G protein-coupled receptor	0.122
Neurotensin receptor 2	NTSR2	Family A G protein-coupled receptor	0.122
HLA class II histocompatibility antigen DRB3-1	HLA-DRB3	Surface antigen	0.122
Cyclin-dependent kinase 2/cyclin A	CDK2, CCNA1, CCNA2	Other cytosolic protein	0.122