Genetic, individual, and familial risk correlates of brain network controllability in major depressive disorder

Demographic effects

First, we examined whether chronological age and gender are associated with controllability as has been shown before [23, 51]. Indeed, we find that the whole-brain average controllability was negatively correlated with age for both healthy controls (f(1.811) = 24.47, p< 0.001, ηp2= 0.029292 [0.012970, 0.051426]) and MDD patients (f (1.686) = 15.08, p< 0.001, ηp2= 0.021505 [0.007166, 0.043462]). Likewise, the regional average controllability varied significantly with age in 30 and 35 different regions for healthy controls and MDD patients, respectively (all p< 0.05, FDR-corrected; for a full list of regions for all analyzes yielding significant regional associations, see Supplementary Results Tables S1 to S16). Whole-brain modal controllability was positively correlated with age for both healthy controls (f(1.811) = 3.93, p= 0.048, ηp2= 0.004821 [0.000101, 0.016141]) and showed a similar trend in MDD patients (f(1.685) = 2.91, p= 0.089, ηp2= 0.004229 [0.000124, 0.015783]). Regional modal controllability significantly varied with age in 33 regions for both healthy controls and MDD patients (all p < 0.05, FDR-corrected). Gender was not significantly associated with whole-brain average controllabilityfor healthy controls (f (1.814) = 0.04, p= 0.839, ηp2= 0.000051 [0.000004, 0.004761]) or MDD patients (f (1.687) = 0.08, p= 0.773, ηp2= 0.000121 [0.000003, 0.006214]). In contrast, regional average controllability significantly varied with gender in 12 and 13 regions for healthy controls and MDD patients, respectively (all p < 0.05, FDR corrected). Whole-brain modal controllability was higher in males than in females for healthy controls (f(1.814) = 7.58, p = 0.006, ηp2= 0.009231 [0.001672, 0.022200]) and showed a similar trend in MDD patients (f(1.687) = 3.73, p = 0.054, ηp2= 0.005397 [0.000222, 0.019111]). Regional modal controllability significantly varied with age in 16 and 18 regions for healthy controls and MDD patients, respectively (all p< 0.05, FDR corrected).

Disease-related variation

Focusing specifically on controllability in MDD, we show that patients displayed lower whole-brain modal controllability (f(1.1505) = 7.96, p = 0.005, ηp2= 0.005261 [0.001227, 0.012531]) than healthy controls. Correspondingly, we observed a non-significant trend towards higher whole-brain average controllabilityvalues ​​in MDD patients (f (1.1505) = 3.08, p= 0.080, ηp2= 0.002041 [0.000056, 0.007247]).

In contrast to previous findings in sub-clinically depressed controls [27]our results do not support an effect of current symptom severity, as measured by the Beck Depression Inventory, on the whole brain average (f(1.671) = 0.19, p = 0.665, ηp2= 0.000279 [0.000005, 0.006632]) or modalcontrollability (f (1.671) = 1.49, p= 0.222, ηp2= 0.002222 [0.000038, 0.011509]) in MDD patients. In line with this observation, the remission status was neither associated with average(f(2.683) = 0.43, p= 0.649, ηp2= 0.001264 [0.000188, 0.013090]) nor modal controllability(f(2.683) = 0.07, p= 0.935, ηp2= 0.000196 [0.000229, 0.009890]) on the whole-brain or regional level in MDD patients. For direct comparison with the previous publication, we also analyzed the healthy controls only: Again, we did not find a significant association between current symptom severity and whole-brain average(f(1.793) = 0.86, p= 0.355, ηp2= 0.001080 [0.000014, 0.008154]) or modal controllability(f(1.793) = 2.32, p= 0.128, ηp2= 0.002923 [0.000053, 0.012674]).

Genetic and familial risk factors

Next, we examined whether controllability in MDD patients is associated with familial risk of MDD and Bipolar Disorder. We show that average controllabilitywas significantly higher in patients carrying self-reported familial risk of MDD (f(1.685) = 4.87, p= 0.028, ηp2= 0.007064 [0.000485, 0.022823]), mirroring the trend-wise increased average controllability of MDD patients compared to healthy controls. This was not the case for modal controllability(f(1.685) = 2.40, p= 0.122, ηp2= 0.003492 [0.000070, 0.015817]).

Average controllabilitywas also higher in patients carrying a familial risk of Bipolar Disorder (f(1.685) = 10.30, p= 0.001, ηp2= 0.014809 [0.002123, 0.038855]) with regional effects in the right supramarginal gyrus, right inferior parietal gyrus, and precuneus. Likewise, whole brain modal controllabilitywas lower in patients carrying a familial risk of Bipolar Disorder (f(1.685) = 9.69, p= 0.002, ηp2= 0.013951 [0.002281, 0.033644]) with regional effects in the right supramarginal gyrus (for detailed regional analyses, see the Supplementary Tables S15 and S16).

Building on this evidence, we extended the analysis to polygenic risk scores and show that polygenic risk scores for MDD [26] were negatively associated with modal controllability (f(1.624) = 4.88, p= 0.028, ηp2= 0.007757 [0.000446, 0.024640]). Likewise, polygenic risk scores for cross-disorder risk [28] were also negatively associated with whole-brain modal controllability (f(1.623) = 4.17, p= 0.042, ηp2= 0.006650 [0.000322, 0.021361]). In addition, we show that polygenic risk scores for MDD [26] were positively correlated with average controllability (f(1.623) = 3.86, p= 0.050, ηp2= 0.006164 [0.000287, 0.021261]). Polygenic risk scores for cross-disorder risk [28] were not significantly associated with whole-brain average controllability (f(1.622) = 0.99, p= 0.320, ηp2= 0.001590 [0.000012, 0.011372]).

In contrast to the observed effect for familial risk of Bipolar Disorder, we neither found a significant association of average (f(1.624) = 0.21, p= 0.644, ηp2= 0.000342 [0.000006, 0.007621]) nor modal controllability (f(1.623) = 0.00, p= 0.990, ηp2= 0.000000 [0.000011, 0.007404]) with polygenic risk score for Bipolar Disorder [30].

Body mass index

With mounting evidence pointing towards brain-structural deviations relating body mass index and MDD [32, 33], we examined the effects of body mass index on controllability. For average controllability, we found associations in 9 regions (p< .05, FDR corrected) including negative correlations in the left superior frontal and posterior cingulate gyrus as well as positive correlations in the superior temporal and left lingual gyrus (see Supplementary Tables S13 and S14). With positive and negative regional associations, a whole-brain effect was absent (f(1.643) = 0.31, p= 0.579, ηp2= 0.000478 [0.000008, 0.007147]). Analyzes of modal controllability revealed the involvement of 6 regions (p< 0.05, FDR-corrected) showing a similar set of regions including the left superior frontal, posterior cingulate, and superior temporal gyrus with—as expected—a switched direction of correlations and, again, no consistent whole-brain effect (f(1.684) = 1.10, p= 0.294, ηp2= 0.001611 [0.000014, 0.011596]).

To assess the specificity of our results, we also tested for the association with height and participant order of inclusion in the study. Neither height (modal controllability: f(1.1410) = 0.88, p= 0.349, ηp2= 0.000622 [0.000008, 0.004492]) nor order of inclusion (f(1.1410) = 0.41, p= 0.522, ηp2= 0.000290 [0.000004, 0.003831]) showed any significant effects on the whole-brain or on the regional level.

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