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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

Effects of FREM3 rs7676614 genotype on reaction times in the perceptual face matching task. Increasing number of A alleles was associated with slower reaction times in the Faces (A), but not the Shapes (C) condition. These results were confirmed in a G allele dominant model, where A homozygotes showed slower reaction times than G carriers in the Faces (B) but not the Shapes condition (D). Error bars represent standard error of the mean. *p < 0.05, #p < 0.10.
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Figure 3: Effects of FREM3 rs7676614 genotype on reaction times in the perceptual face matching task. Increasing number of A alleles was associated with slower reaction times in the Faces (A), but not the Shapes (C) condition. These results were confirmed in a G allele dominant model, where A homozygotes showed slower reaction times than G carriers in the Faces (B) but not the Shapes condition (D). Error bars represent standard error of the mean. *p < 0.05, #p < 0.10.

Mentions: In addition to its effect on amygdala response, FREM3 genotype was found to modulate processing speed as indexed by behavioral measures collected during the BOLD fMRI paradigm. Specifically, increasing number of A alleles was associated with slower RTs in the Faces (b = −0.107, p = 0.035; controlling for gender and age: b = −0.109, p = 0.032), but not in the Shapes (p>0.2; Figures 3A,C) condition. Similarly, G allele carriers had faster RTs relative to A homozygotes in the Faces [A homozygotes: 1.22 ± 0.28 s; G carriers: 1.15 ± 0.27 s; F(1, 363) = 4.89, p = 0.028; controlling for gender and age: F(1, 361) = 5.00, p = 0.026], but not in the Shapes blocks [A homozygotes: 0.96 ± 0.19 s; G carriers: 0.93 ± 0.19 s; F(1, 363) = 1.97, p = 0.161; controlling for gender and age: F(1, 361) = 2.22, p = 0.137; Figures 3B,D]. Notably, RTs were slower overall in the Faces, compared to the Shapes condition, possibly reflecting the relative perceptual complexity of the stimuli to be matched [Faces: 1.80 ± 0.28 s; Shapes: 0.94 ± 0.19 s F(1, 361) = 0.826, p < 0.0001]. Thus, perhaps the lack of genotype effect on RT in the Shapes condition may reflect performance ceiling effects. There were no differences in accuracy between genotype groups (p>0.27).


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)

Effects of FREM3 rs7676614 genotype on reaction times in the perceptual face matching task. Increasing number of A alleles was associated with slower reaction times in the Faces (A), but not the Shapes (C) condition. These results were confirmed in a G allele dominant model, where A homozygotes showed slower reaction times than G carriers in the Faces (B) but not the Shapes condition (D). Error bars represent standard error of the mean. *p < 0.05, #p < 0.10.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Effects of FREM3 rs7676614 genotype on reaction times in the perceptual face matching task. Increasing number of A alleles was associated with slower reaction times in the Faces (A), but not the Shapes (C) condition. These results were confirmed in a G allele dominant model, where A homozygotes showed slower reaction times than G carriers in the Faces (B) but not the Shapes condition (D). Error bars represent standard error of the mean. *p < 0.05, #p < 0.10.
Mentions: In addition to its effect on amygdala response, FREM3 genotype was found to modulate processing speed as indexed by behavioral measures collected during the BOLD fMRI paradigm. Specifically, increasing number of A alleles was associated with slower RTs in the Faces (b = −0.107, p = 0.035; controlling for gender and age: b = −0.109, p = 0.032), but not in the Shapes (p>0.2; Figures 3A,C) condition. Similarly, G allele carriers had faster RTs relative to A homozygotes in the Faces [A homozygotes: 1.22 ± 0.28 s; G carriers: 1.15 ± 0.27 s; F(1, 363) = 4.89, p = 0.028; controlling for gender and age: F(1, 361) = 5.00, p = 0.026], but not in the Shapes blocks [A homozygotes: 0.96 ± 0.19 s; G carriers: 0.93 ± 0.19 s; F(1, 363) = 1.97, p = 0.161; controlling for gender and age: F(1, 361) = 2.22, p = 0.137; Figures 3B,D]. Notably, RTs were slower overall in the Faces, compared to the Shapes condition, possibly reflecting the relative perceptual complexity of the stimuli to be matched [Faces: 1.80 ± 0.28 s; Shapes: 0.94 ± 0.19 s F(1, 361) = 0.826, p < 0.0001]. Thus, perhaps the lack of genotype effect on RT in the Shapes condition may reflect performance ceiling effects. There were no differences in accuracy between genotype groups (p>0.27).

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