Race, genetic ancestry and response to antidepressant treatment for major depression

Abstract

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study revealed poorer antidepressant treatment response among black compared with white participants. This racial disparity persisted even after socioeconomic and baseline clinical factors were taken into account. Some studies have suggested genetic contributions to this disparity, but none have attempted to disentangle race and genetic ancestry. Here we used genome-wide single-nucleotide polymorphism (SNP) data to examine independent contributions of race and genetic ancestry to citalopram response. Secondary data analyses included 1877 STAR*D participants who completed an average of 10 weeks of citalopram treatment and provided DNA samples. Participants reported their race as White (n=1464), black (n=299) or other/mixed (n=114). Genetic ancestry was estimated by multidimensional scaling (MDS) analyses of about 500 000 SNPs. Ancestry proportions were estimated by STRUCTURE. Structural equation modeling was used to examine the direct and indirect effects of observed and latent predictors of response, defined as change in the Quick Inventory of Depressive Symptomatology (QIDS) score from baseline to exit. Socioeconomic and baseline clinical factors, race, and anxiety significantly predicted response, as previously reported. However, direct effects of race disappeared in all models that included genetic ancestry. Genetic African ancestry predicted lower treatment response in all models. Although socioeconomic and baseline clinical factors drive racial differences in antidepressant response, genetic ancestry, rather than self-reported race, explains a significant fraction of the residual differences. Larger samples would be needed to identify the specific genetic mechanisms that may be involved, but these findings underscore the importance of including more African-American patients in drug trials.

Trial registration: ClinicalTrials.gov NCT00021528.

Figures

Figure 1

(a) Genetic ancestry cluster dimensions among the self-reported racial groups. X-axis shows scores along C1 dimension depicting African ancestry, whereas Y-axis shows scores along C2 dimension depicting European ancestry. The other clusters (C3 and C4) obtained from MDS analyses failed to differentiate along genetic ancestry dimensions and therefore are not depicted in the figure. (b) STAR*D genetic ancestry clusters with HapMap phase III reference panels. ASW, African ancestry in Southwest USA; CEU, Utah residents with northern and western European ancestry (CEPH); CHD, Chinese in metropolitan Denver, Colorado; GIH, Gujarati Indians in Houston, Texas; JPT, Japanese in Tokyo; LWK, Luhya in Webuye, Kenya; MEX, Mexican ancestry in Los Angeles, California; MKK, Masai in Kinyawa, Kenya; STARD_EU/STARD_AA/STARD_OT, self-reported White/Black or African American/other race in STARD*D sample; TSI, Tuscans in Italy: CHB, Han Chinese in Beijing: and YRI, Yoruba in Ibadan, Nigeria.

Figure 2

Effect of genetic ancestry, self-reported race, and clinical and social factors on treatment response. The diagram refers to model 2 as described in the text. Only coefficients for significant direct paths (at the p<0.05 level (two-tailed)) to treatment response are depicted. For all models, regression coefficients use standardized units, ie, the effect of one SD change in predictors on SD change in treatment response, and are comparable across predictors.

Figure 3

Effects of genetic ancestry, self-reported race, and anxiety on treatment response. The diagram refers to model 4 as described in the text. Direct effects are represented by straight arrows and indirect (mediator) effects are represented by curved arrows. For all models, coefficients (rounded to the nearest hundredth) represent standardized units, ie, the effect of one SD change in predictors on SD change in treatment response, and are comparable within models across predictors. All coefficients in bold are significant at p<0.05 level (two-tailed). Genetic ancestry: total effects=−0.129***, direct effects=−0.100**, and indirect effects=−0.029); self-reported race: total effects=0.017, direct effects=0.017, and indirect effects=N/A; anxiety: total effects=−0.174***, direct effects=−0.174, and indirect effects=N/A. When HRSD17 is included as part of treatment response, the impact of genetic ancestry on TR is −0.108 (p<0.01); the impact of self-reported race is 0.014 (p>0.500); and the impact of anxiety on TR is −0.156 (p<0.001).