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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

Statistical parametric map illustrating mean bilateral activity for the Faces > Shapes contrast. Activation clusters are presented for (A) the amygdala (peak voxel activation in the left hemisphere: x = −22, y = −6, z = −18, t = 28.55, p < 0.000001, kE = 179; right hemisphere: x = 28, y = −4, z = −20, t = 32.82, p < 0.000001, kE = 199) and (B) Brodmann areas 11 and 47 (peak voxel activation in the left hemisphere: x = 58, y = 28, z = 0, t = 15.60, p < 0.000001, kE = 143; right hemisphere: x = −52, y = 40, z = −2, t = 14.47, p < 0.000001, kE = 24). The clusters are overlaid onto canonical structural brain images in the coronal plane (y = −2) and axial planes (z = −12), respectively.
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Figure 1: Statistical parametric map illustrating mean bilateral activity for the Faces > Shapes contrast. Activation clusters are presented for (A) the amygdala (peak voxel activation in the left hemisphere: x = −22, y = −6, z = −18, t = 28.55, p < 0.000001, kE = 179; right hemisphere: x = 28, y = −4, z = −20, t = 32.82, p < 0.000001, kE = 199) and (B) Brodmann areas 11 and 47 (peak voxel activation in the left hemisphere: x = 58, y = 28, z = 0, t = 15.60, p < 0.000001, kE = 143; right hemisphere: x = −52, y = 40, z = −2, t = 14.47, p < 0.000001, kE = 24). The clusters are overlaid onto canonical structural brain images in the coronal plane (y = −2) and axial planes (z = −12), respectively.

Mentions: Consistent with prior research (Nikolova and Hariri, 2012; Swartz et al., 2015), our task resulted in significant amygdala reactivity bilaterally for the Faces > Shapes contrast (Figure 1A). Further analyses revealed significant activity in BA11 and BA47 (Figure 1B). Partially confirming prior work (Nikolova et al., 2012), we found that men had greater amygdala reactivity than women in the left [t(363) = 2.54, p = 0.012], but not the right hemisphere [t(363) = 1.30, p = 0.193]. When gender was accounted for, amygdala reactivity was further modulated by age, such that older participants showed a trend towards lower amygdala reactivity (left hemisphere: b = −0.087, p = 0.096; right hemisphere: b = −0.090, p = 0.085). There were no differences in age, gender composition and estimated IQ among genotype groups (Table 1). However, in light of the effects of gender and age on amygdala reactivity, all analyses were conducted with and without gender and age as covariates.


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)

Statistical parametric map illustrating mean bilateral activity for the Faces > Shapes contrast. Activation clusters are presented for (A) the amygdala (peak voxel activation in the left hemisphere: x = −22, y = −6, z = −18, t = 28.55, p < 0.000001, kE = 179; right hemisphere: x = 28, y = −4, z = −20, t = 32.82, p < 0.000001, kE = 199) and (B) Brodmann areas 11 and 47 (peak voxel activation in the left hemisphere: x = 58, y = 28, z = 0, t = 15.60, p < 0.000001, kE = 143; right hemisphere: x = −52, y = 40, z = −2, t = 14.47, p < 0.000001, kE = 24). The clusters are overlaid onto canonical structural brain images in the coronal plane (y = −2) and axial planes (z = −12), respectively.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Statistical parametric map illustrating mean bilateral activity for the Faces > Shapes contrast. Activation clusters are presented for (A) the amygdala (peak voxel activation in the left hemisphere: x = −22, y = −6, z = −18, t = 28.55, p < 0.000001, kE = 179; right hemisphere: x = 28, y = −4, z = −20, t = 32.82, p < 0.000001, kE = 199) and (B) Brodmann areas 11 and 47 (peak voxel activation in the left hemisphere: x = 58, y = 28, z = 0, t = 15.60, p < 0.000001, kE = 143; right hemisphere: x = −52, y = 40, z = −2, t = 14.47, p < 0.000001, kE = 24). The clusters are overlaid onto canonical structural brain images in the coronal plane (y = −2) and axial planes (z = −12), respectively.
Mentions: Consistent with prior research (Nikolova and Hariri, 2012; Swartz et al., 2015), our task resulted in significant amygdala reactivity bilaterally for the Faces > Shapes contrast (Figure 1A). Further analyses revealed significant activity in BA11 and BA47 (Figure 1B). Partially confirming prior work (Nikolova et al., 2012), we found that men had greater amygdala reactivity than women in the left [t(363) = 2.54, p = 0.012], but not the right hemisphere [t(363) = 1.30, p = 0.193]. When gender was accounted for, amygdala reactivity was further modulated by age, such that older participants showed a trend towards lower amygdala reactivity (left hemisphere: b = −0.087, p = 0.096; right hemisphere: b = −0.090, p = 0.085). There were no differences in age, gender composition and estimated IQ among genotype groups (Table 1). However, in light of the effects of gender and age on amygdala reactivity, all analyses were conducted with and without gender and age as covariates.

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