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FRAS1-related extracellular matrix 3 (FREM3) single-nucleotide polymorphism effects on gene expression, amygdala reactivity and perceptual processing speed: An accelerated aging pathway of depression risk.

Nikolova YS, Iruku SP, Lin CW, Conley ED, Puralewski R, French B, Hariri AR, Sibille E - Front Psychol (2015)

Bottom Line: In the postmortem cohort, the T allele of rs6537170 (proxy for the rs7676614 A allele), was associated with trend-level reductions in gene expression in Brodmann areas 11 and 47 (p = 0.066), reminiscent of patterns characteristic of older age.The low-expressing allele of another FREM3 SNP (rs1391187) was similarly associated with reduced amygdala reactivity and slower TMT Part B speed, in addition to reduced BA47 activity and extraversion (p < 0.05).Together, these results suggest common genetic variation associated with reduced FREM3 expression may confer risk for a subtype of depression characterized by reduced reactivity to environmental stimuli and slower perceptual processing speed, possibly suggestive of accelerated aging.

View Article: PubMed Central - PubMed

Affiliation: Campbell Family Mental Health Research Institute of CAMH Toronto, ON, Canada.

ABSTRACT
The A allele of the FRAS1-related extracellular matrix protein 3 (FREM3) rs7676614 single nucleotide polymorphism (SNP) was linked to major depressive disorder (MDD) in an early genome-wide association study (GWAS), and to symptoms of psychomotor retardation in a follow-up investigation. In line with significant overlap between age- and depression-related molecular pathways, parallel work has shown that FREM3 expression in postmortem human brain decreases with age. Here, we probe the effect of rs7676614 on amygdala reactivity and perceptual processing speed, both of which are altered in depression and aging. Amygdala reactivity was assessed using a face-matching BOLD fMRI paradigm in 365 Caucasian participants in the Duke Neurogenetics Study (DNS) (192 women, mean age 19.7 ± 1.2). Perceptual processing speed was indexed by reaction times in the same task and the Trail Making Test (TMT). The effect of rs7676614 on FREM3 mRNA brain expression levels was probed in a postmortem cohort of 169 Caucasian individuals (44 women, mean age 50.8 ± 14.9). The A allele of rs7676614 was associated with blunted amygdala reactivity to faces, slower reaction times in the face-matching condition (p < 0.04), as well as marginally slower performance on TMT Part B (p = 0.056). In the postmortem cohort, the T allele of rs6537170 (proxy for the rs7676614 A allele), was associated with trend-level reductions in gene expression in Brodmann areas 11 and 47 (p = 0.066), reminiscent of patterns characteristic of older age. The low-expressing allele of another FREM3 SNP (rs1391187) was similarly associated with reduced amygdala reactivity and slower TMT Part B speed, in addition to reduced BA47 activity and extraversion (p < 0.05). Together, these results suggest common genetic variation associated with reduced FREM3 expression may confer risk for a subtype of depression characterized by reduced reactivity to environmental stimuli and slower perceptual processing speed, possibly suggestive of accelerated aging.

No MeSH data available.


Related in: MedlinePlus

Results from mediation models wherein activity in BA47 mediated the association between rs1909022 genotype and extraversion scores by itself (A) or in conjunction with amygdala reactivity (B). Raw regression coefficients are presented for each path, along with standard errors in parentheses. Bootstrapped 95% confidence intervals are presented for the indirect (mediation) effects. **p < 0.005, *p < 0.05, #p < 0.10. CI, Confidence interval.
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Figure 8: Results from mediation models wherein activity in BA47 mediated the association between rs1909022 genotype and extraversion scores by itself (A) or in conjunction with amygdala reactivity (B). Raw regression coefficients are presented for each path, along with standard errors in parentheses. Bootstrapped 95% confidence intervals are presented for the indirect (mediation) effects. **p < 0.005, *p < 0.05, #p < 0.10. CI, Confidence interval.

Mentions: Although there were no differences in measures of current mood and neuroticism between genotype groups as defined by either SNP (p>0.10), increasing number of major alleles at rs1391187/rs1909022 was associated with lower extraversion, as assessed by the NEOE (no covariates: b = −0.121, p = 0.021, with covariates; b = −0.124, p = 0.017, Figure 7B). This effect was driven primarily by the Activity subscale (no covariates: b = −0.143, p = 0.006; with covariates: b = −0.145, p = 0.005). Furthermore, NEOE was positively correlated with BA47 activity in the left hemisphere, such that BA47 activity negatively mediated the association between number of rs1391187/rs1909022 major alleles and NEOE scores (Figure 8A). Finally, there was a positive correlation between amygdala reactivity and BA47, such that when amygdala and BA47 activity were entered sequentially into a mediation model, they were both found to be significant mediators of the link between rs1391187/rs1909022 genotype and NEOE (Figure 8B). Importantly, a model where amygdala reactivity was entered as a mediator more proximal to extraversion did not result in significant mediation (b = 0.098, SE = 0.264, 95% CI: –0.366, 0.704).


FRAS1-related extracellular matrix 3 (FREM3) single-nucleotide polymorphism effects on gene expression, amygdala reactivity and perceptual processing speed: An accelerated aging pathway of depression risk.

Nikolova YS, Iruku SP, Lin CW, Conley ED, Puralewski R, French B, Hariri AR, Sibille E - Front Psychol (2015)

Results from mediation models wherein activity in BA47 mediated the association between rs1909022 genotype and extraversion scores by itself (A) or in conjunction with amygdala reactivity (B). Raw regression coefficients are presented for each path, along with standard errors in parentheses. Bootstrapped 95% confidence intervals are presented for the indirect (mediation) effects. **p < 0.005, *p < 0.05, #p < 0.10. CI, Confidence interval.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4584966&req=5

Figure 8: Results from mediation models wherein activity in BA47 mediated the association between rs1909022 genotype and extraversion scores by itself (A) or in conjunction with amygdala reactivity (B). Raw regression coefficients are presented for each path, along with standard errors in parentheses. Bootstrapped 95% confidence intervals are presented for the indirect (mediation) effects. **p < 0.005, *p < 0.05, #p < 0.10. CI, Confidence interval.
Mentions: Although there were no differences in measures of current mood and neuroticism between genotype groups as defined by either SNP (p>0.10), increasing number of major alleles at rs1391187/rs1909022 was associated with lower extraversion, as assessed by the NEOE (no covariates: b = −0.121, p = 0.021, with covariates; b = −0.124, p = 0.017, Figure 7B). This effect was driven primarily by the Activity subscale (no covariates: b = −0.143, p = 0.006; with covariates: b = −0.145, p = 0.005). Furthermore, NEOE was positively correlated with BA47 activity in the left hemisphere, such that BA47 activity negatively mediated the association between number of rs1391187/rs1909022 major alleles and NEOE scores (Figure 8A). Finally, there was a positive correlation between amygdala reactivity and BA47, such that when amygdala and BA47 activity were entered sequentially into a mediation model, they were both found to be significant mediators of the link between rs1391187/rs1909022 genotype and NEOE (Figure 8B). Importantly, a model where amygdala reactivity was entered as a mediator more proximal to extraversion did not result in significant mediation (b = 0.098, SE = 0.264, 95% CI: –0.366, 0.704).

Bottom Line: In the postmortem cohort, the T allele of rs6537170 (proxy for the rs7676614 A allele), was associated with trend-level reductions in gene expression in Brodmann areas 11 and 47 (p = 0.066), reminiscent of patterns characteristic of older age.The low-expressing allele of another FREM3 SNP (rs1391187) was similarly associated with reduced amygdala reactivity and slower TMT Part B speed, in addition to reduced BA47 activity and extraversion (p < 0.05).Together, these results suggest common genetic variation associated with reduced FREM3 expression may confer risk for a subtype of depression characterized by reduced reactivity to environmental stimuli and slower perceptual processing speed, possibly suggestive of accelerated aging.

View Article: PubMed Central - PubMed

Affiliation: Campbell Family Mental Health Research Institute of CAMH Toronto, ON, Canada.

ABSTRACT
The A allele of the FRAS1-related extracellular matrix protein 3 (FREM3) rs7676614 single nucleotide polymorphism (SNP) was linked to major depressive disorder (MDD) in an early genome-wide association study (GWAS), and to symptoms of psychomotor retardation in a follow-up investigation. In line with significant overlap between age- and depression-related molecular pathways, parallel work has shown that FREM3 expression in postmortem human brain decreases with age. Here, we probe the effect of rs7676614 on amygdala reactivity and perceptual processing speed, both of which are altered in depression and aging. Amygdala reactivity was assessed using a face-matching BOLD fMRI paradigm in 365 Caucasian participants in the Duke Neurogenetics Study (DNS) (192 women, mean age 19.7 ± 1.2). Perceptual processing speed was indexed by reaction times in the same task and the Trail Making Test (TMT). The effect of rs7676614 on FREM3 mRNA brain expression levels was probed in a postmortem cohort of 169 Caucasian individuals (44 women, mean age 50.8 ± 14.9). The A allele of rs7676614 was associated with blunted amygdala reactivity to faces, slower reaction times in the face-matching condition (p < 0.04), as well as marginally slower performance on TMT Part B (p = 0.056). In the postmortem cohort, the T allele of rs6537170 (proxy for the rs7676614 A allele), was associated with trend-level reductions in gene expression in Brodmann areas 11 and 47 (p = 0.066), reminiscent of patterns characteristic of older age. The low-expressing allele of another FREM3 SNP (rs1391187) was similarly associated with reduced amygdala reactivity and slower TMT Part B speed, in addition to reduced BA47 activity and extraversion (p < 0.05). Together, these results suggest common genetic variation associated with reduced FREM3 expression may confer risk for a subtype of depression characterized by reduced reactivity to environmental stimuli and slower perceptual processing speed, possibly suggestive of accelerated aging.

No MeSH data available.


Related in: MedlinePlus