Table 2.

Association Analysis of all Relevant DME Genetic Effects on Optimized Dose in Univariate and Covariance Analyses

Drug group	Gene & variant	Main effect		Analysis of covariance
		Effect size †	p-value	p-value
Perphenazine	CYP2D6_combined	β = +0.33	0.30	0.22
	CYP1A2*1F	β= +0.17	0.30	*
	CYP2C8_combined	β= −0.33	0.13	*
	CYP2C9_combined	β= −0.08	0.71	*
	CYP2C19*2	β= −0.001	0.99	*
Risperidone	CYP2D6_combined	β = −0.07	0.64	0.17
	CYP3A5_combined	β= −0.12	0.24	0.49
	CYP3A4*1B	β= −0.06	0.53	*
	ABCB1_combined	β= −0.12	0.20	0.81
Olanzapine	CYP1A2*1F	β= −0.15	0.11	0.08
	FMO3_combined	β= −0.05	0.56	0.54
	UGT1A4_combined	β= +0.07	0.58	*
	CYP3A5_combined	β= −0.002	0.98	*
	CYP1A4*1B	β= +0.08	0.35	*
	CYP2D6_combined	β = −0.06	0.64	*
Quetiapine	CYP3A5_combined	β= +0.03	0.79	0.46
	CYP3A4*1B	β= +0.05	0.60	*
	ABCB1_combined	β= −0.001	0.99	*
	CYP2D6_combined	β = −0.04	0.78	*
	CYP2C9_combined	β= −0.01	0.94	*
Ziprasidone	CYP3A5_combined	β= −0.15	0.21	0.34‡
	CYP3A4*1B	β= −0.1	0.40	*
	ABCB1_combined	β= +0.02	0.88	*

β is the slope of the linear regression model defined by Y = α + β × X, where Y is optimized dose and X is the genetic factor tested. Annotation of “gene_combined” relates to the sum functionality of the gene as reflected by the two haplotypes individuals carry (defined in Supplementary Materials and Methods, Table 3).

^*Asterisks denote variants which were considered as potential covariates in the step-wise regression model.

Nominal p-values are reported.

^†Main effects are registered in reference to the lower/absent enzymatic activity genotypes, expecting the effect to be positive (i.e. lower activity genotypes are expected to settle on lower optimized doses).

^‡Race-by-gene interaction term was statistically significant (p=0.04) in the ziprasidone cohort, but a multivariate analysis in each race group separately yielded p= 0.36 and 0.12 for African-Americans and Caucasians, respectively.