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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 amygdala reactivity. Increasing number of A alleles was associated with decreased amygdala reactivity in the left (A) and right (C) hemisphere. In a G allele dominant model, A homozygotes showed a trend toward decreased amygdala reactivity in the left hemisphere (B) and significantly decreased amygdala reactivity than G carriers in the right hemisphere (D). Error bars represent standard error of the mean. *p < 0.05, #p < 0.10, a.u. = arbitrary units.
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Figure 2: Effects of FREM3 rs7676614 genotype on amygdala reactivity. Increasing number of A alleles was associated with decreased amygdala reactivity in the left (A) and right (C) hemisphere. In a G allele dominant model, A homozygotes showed a trend toward decreased amygdala reactivity in the left hemisphere (B) and significantly decreased amygdala reactivity than G carriers in the right hemisphere (D). Error bars represent standard error of the mean. *p < 0.05, #p < 0.10, a.u. = arbitrary units.

Mentions: FREM3 rs7676614 genotype modulated amygdala response, such that increasing number of major (A) alleles was associated with significantly decreased amygdala reactivity in the right (b = −0.109, p = 0.038), and marginally decreased reactivity in the left (b = −0.101, p = 0.055) hemisphere (Figures 2A,C). The effect was significant bilaterally when covarying for gender and age (right hemisphere: b = −0.116, p = 0.026; left hemisphere: b = −0.110, p = 0.035). When a G allele dominant model was tested, individuals homozygous for the risk A allele were found to have relatively reduced amygdala reactivity for the All Faces > Shapes contrast, when compared to carriers of the G allele. The effect was stronger on the right side [left hemisphere: F(1, 363) = 3.06, p = 0.081; right hemisphere: F(1, 363) = 4.46, p = 0.035; Figures 2B,D]. The significance of these results did not change when gender and age were controlled for [left hemisphere: F(1, 361) = 3.85, p = 0.051; right hemisphere: F(1, 361) = 5.20, p = 0.023]. Notably, no significant effect of genotype emerged in threat-specific contrasts (p>0.11), suggesting a broader hypo-reactivity of the amygdala to environmental salience rather than a threat-specific blunting of amygdala response. Consistent with this conceptualization, neither current, nor early life stress interacted with FREM3 genotype to predict amygdala response (p>0.12). Importantly, there were no differences in self-reported early or recent stress between genotype groups (p>0.10).


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 amygdala reactivity. Increasing number of A alleles was associated with decreased amygdala reactivity in the left (A) and right (C) hemisphere. In a G allele dominant model, A homozygotes showed a trend toward decreased amygdala reactivity in the left hemisphere (B) and significantly decreased amygdala reactivity than G carriers in the right hemisphere (D). Error bars represent standard error of the mean. *p < 0.05, #p < 0.10, a.u. = arbitrary units.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Effects of FREM3 rs7676614 genotype on amygdala reactivity. Increasing number of A alleles was associated with decreased amygdala reactivity in the left (A) and right (C) hemisphere. In a G allele dominant model, A homozygotes showed a trend toward decreased amygdala reactivity in the left hemisphere (B) and significantly decreased amygdala reactivity than G carriers in the right hemisphere (D). Error bars represent standard error of the mean. *p < 0.05, #p < 0.10, a.u. = arbitrary units.
Mentions: FREM3 rs7676614 genotype modulated amygdala response, such that increasing number of major (A) alleles was associated with significantly decreased amygdala reactivity in the right (b = −0.109, p = 0.038), and marginally decreased reactivity in the left (b = −0.101, p = 0.055) hemisphere (Figures 2A,C). The effect was significant bilaterally when covarying for gender and age (right hemisphere: b = −0.116, p = 0.026; left hemisphere: b = −0.110, p = 0.035). When a G allele dominant model was tested, individuals homozygous for the risk A allele were found to have relatively reduced amygdala reactivity for the All Faces > Shapes contrast, when compared to carriers of the G allele. The effect was stronger on the right side [left hemisphere: F(1, 363) = 3.06, p = 0.081; right hemisphere: F(1, 363) = 4.46, p = 0.035; Figures 2B,D]. The significance of these results did not change when gender and age were controlled for [left hemisphere: F(1, 361) = 3.85, p = 0.051; right hemisphere: F(1, 361) = 5.20, p = 0.023]. Notably, no significant effect of genotype emerged in threat-specific contrasts (p>0.11), suggesting a broader hypo-reactivity of the amygdala to environmental salience rather than a threat-specific blunting of amygdala response. Consistent with this conceptualization, neither current, nor early life stress interacted with FREM3 genotype to predict amygdala response (p>0.12). Importantly, there were no differences in self-reported early or recent stress between genotype groups (p>0.10).

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