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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 TMT performance. Relative to G carriers, A allele homozygotes showed a trend toward slower performance in both Part A (A) and Part B (B) of the TMT. Error bars represent standard error of the mean. *p < 0.05, #p < 0.10.
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Figure 4: Effects of FREM3 rs7676614 genotype on TMT performance. Relative to G carriers, A allele homozygotes showed a trend toward slower performance in both Part A (A) and Part B (B) of the TMT. Error bars represent standard error of the mean. *p < 0.05, #p < 0.10.

Mentions: To further probe the effect of FREM3 genotype on perceptual processing speed, we compared genotype groups on their performance on the TMT Parts A and B, administered outside the scanner. Despite A homozygotes' being nominally slower to complete Trails A, the difference in performance reached only trend levels [A homozygotes: 22.71 ± 6.60 s; G carriers: 21.64 ± 5.79 s, F(1, 355) = 3.11, p = 0.079; Figure 4A]. Larger genotype differences emerged in Trails B performance, where A homozygotes were slower to complete the task by an average of 2.14 s [A homozygotes: 46.02 ± 12.73 s; G carriers: 43.89 ± 11.03 s, F(1, 355) = 3.69, p = 0.056; Figure 4B]. No additive effect of number of A alleles was observed on either task (p>0.12). Notably, there were no genotype effects on number of errors in either Trails A or Trails B (p>0.39) and the differences in speed occurred in the absence of genotype differences in estimated IQ (Table 1). Furthermore, the effects remained trending when IQ was controlled for alongside gender and age (Trails A: p = 0.089; Trails B: p = 0.076).


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 TMT performance. Relative to G carriers, A allele homozygotes showed a trend toward slower performance in both Part A (A) and Part B (B) of the TMT. Error bars represent standard error of the mean. *p < 0.05, #p < 0.10.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Effects of FREM3 rs7676614 genotype on TMT performance. Relative to G carriers, A allele homozygotes showed a trend toward slower performance in both Part A (A) and Part B (B) of the TMT. Error bars represent standard error of the mean. *p < 0.05, #p < 0.10.
Mentions: To further probe the effect of FREM3 genotype on perceptual processing speed, we compared genotype groups on their performance on the TMT Parts A and B, administered outside the scanner. Despite A homozygotes' being nominally slower to complete Trails A, the difference in performance reached only trend levels [A homozygotes: 22.71 ± 6.60 s; G carriers: 21.64 ± 5.79 s, F(1, 355) = 3.11, p = 0.079; Figure 4A]. Larger genotype differences emerged in Trails B performance, where A homozygotes were slower to complete the task by an average of 2.14 s [A homozygotes: 46.02 ± 12.73 s; G carriers: 43.89 ± 11.03 s, F(1, 355) = 3.69, p = 0.056; Figure 4B]. No additive effect of number of A alleles was observed on either task (p>0.12). Notably, there were no genotype effects on number of errors in either Trails A or Trails B (p>0.39) and the differences in speed occurred in the absence of genotype differences in estimated IQ (Table 1). Furthermore, the effects remained trending when IQ was controlled for alongside gender and age (Trails A: p = 0.089; Trails B: p = 0.076).

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