Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach

BMC Genomics

Table 1 Suggestive associations of rare variant burden in the ACMG-56 genes with psychiatric disorders

Phenotype	PheCode	Gene	Consequence	Ncase	Ncontrol	Ncase carrier	Ncontrol carrier	OR	95% CI	P-value
Major depressive disorder	296.22	PTEN	Non-synonymous	2312	12,869	8	8	9.15	(3.03, 27.6)	1.5 × 10^–4
Substance addiction and disorders	316	KCNQ1	Damaging missense	446	14,735	4	10	14.63	(4.31, 49.6)	2.4 × 10^–4
Mental retardation	315.3	PKP2	All	123	15,058	5	168	8.32	(3.24, 21.4)	3.0 × 10^–4
Major depressive disorder	296.22	LDLR	Non-synonymous	2312	12,869	35	105	2.10	(1.42, 3.11)	3.6 × 10^–4
Other mental disorder	306	TNNI3	PTV + damaging mis	1759	13,422	3	0	65.85	(1.90, 2279)	4.2 × 10^–4
Depression	296.2	CACNA1S	All	2590	12,591	100	327	1.50	(1.20, 1.88)	5.8 × 10^–4
Tobacco use disorder	318	PKP2	PTV + damaging mis	2783	12,398	5	2	15.98	(2.41, 106)	6.7 × 10^–4
Substance addiction and disorders	316	KCNQ1	PTV + damaging mis	446	14,735	4	14	10.56	(3.36, 33.2)	7.1 × 10^–4
Tobacco use disorder	318	APOB	PTV	2783	12,398	6	2	12.99	(2.19, 76.9)	1.1 × 10^–3
Somatoform disorder	303.4	SDHC	PTV	130	15,051	1	1	160.70	(8.64, 2987)	1.1 × 10^–3
Alcoholism	317.1	DSC2	PTV	334	14,847	2	3	34.33	(4.68, 252)	1.3 × 10^–3

For each gene, a PheWAS was performed to assess the burden of rare variation (MAF < 1%) in 37 mental illnesses (Table S3) using Firth’s logistic regression, adjusting for age, sex, sites, and the first 10 PCs. This analysis was done separately for five groups of qualifying variants (all variants with MAF < 1%, non-synonymous variants, damaging missense variants, protein-truncating variants or PTVs, and PTVs plus damaging missense variants). Shown in the table are suggestive gene-disorder associations at a Bonferroni-corrected significance of 0.05/37 = 1.35 × 10^–3 in an individual PheWAS. “Carrier” is defined as individuals who carried at least one copy of the qualifying variant in the gene. No genes achieved study-wide statistical significance at FDR < 0.05 accounting for all tests. The full set of gene-disorder associations are depicted in Fig. 1. OR odds ratio, CI confidence interval

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