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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 rs1909022 genotype on TMT Part B performance and extraversion. Increasing number of major (G) alleles was associated with relatively slower TMT performance (A) and lower levels of extraversion (B). *p < 0.05.
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Figure 7: Effects of FREM3 rs1909022 genotype on TMT Part B performance and extraversion. Increasing number of major (G) alleles was associated with relatively slower TMT performance (A) and lower levels of extraversion (B). *p < 0.05.

Mentions: To further explore the potential involvement of the FREM3 gene in regulating depression-relevant neural and behavioral phenotypes, we identified rs1391187 as the SNP most strongly modulating FREM3 expression across both BA11 (p = 2.17 × 10−5, Figure 5E) and BA47 (p = 2.47 × 10−6, Figure 5F, Supplementary Table 2) in our postmortem cohort, and tested its effects (via proxy SNP rs1909022, R2 = 1.00, D′ = 1.00), on neural activity and perceptual processing speed in our in vivo cohort. In striking similarly to rs7676614, the lower-expressing major allele at rs1391187/rs1909022 was also associated with reduced amygdala reactivity bilaterally (left amygdala: b = −0.167; p = 0.001; right amygdala: b = −0.159; p = 0.002; Figures 6A,B) as well as slower speed in the TMT Part B (b = 0.114; p = 0.025, Figure 7A). These effects remained significant when controlling for gender and age (left amygdala: b = −0.170; p = 0.001, right amygdala: b = −0.162; p = 0.002; Trails B, adjusted for IQ: b = 0.111; p = 0.028). Notably, there were no significant differences in gender composition or estimated IQ among rs1909022 genotype groups (Table 2). While there was a main effect of age (p = 0.045), such that heterozygotes were slightly but significantly older than GG homozygotes (p = 0.024, LSD-corrected), there was no linear association between number of minor/major alleles and age (p = 0.486).


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 rs1909022 genotype on TMT Part B performance and extraversion. Increasing number of major (G) alleles was associated with relatively slower TMT performance (A) and lower levels of extraversion (B). *p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Effects of FREM3 rs1909022 genotype on TMT Part B performance and extraversion. Increasing number of major (G) alleles was associated with relatively slower TMT performance (A) and lower levels of extraversion (B). *p < 0.05.
Mentions: To further explore the potential involvement of the FREM3 gene in regulating depression-relevant neural and behavioral phenotypes, we identified rs1391187 as the SNP most strongly modulating FREM3 expression across both BA11 (p = 2.17 × 10−5, Figure 5E) and BA47 (p = 2.47 × 10−6, Figure 5F, Supplementary Table 2) in our postmortem cohort, and tested its effects (via proxy SNP rs1909022, R2 = 1.00, D′ = 1.00), on neural activity and perceptual processing speed in our in vivo cohort. In striking similarly to rs7676614, the lower-expressing major allele at rs1391187/rs1909022 was also associated with reduced amygdala reactivity bilaterally (left amygdala: b = −0.167; p = 0.001; right amygdala: b = −0.159; p = 0.002; Figures 6A,B) as well as slower speed in the TMT Part B (b = 0.114; p = 0.025, Figure 7A). These effects remained significant when controlling for gender and age (left amygdala: b = −0.170; p = 0.001, right amygdala: b = −0.162; p = 0.002; Trails B, adjusted for IQ: b = 0.111; p = 0.028). Notably, there were no significant differences in gender composition or estimated IQ among rs1909022 genotype groups (Table 2). While there was a main effect of age (p = 0.045), such that heterozygotes were slightly but significantly older than GG homozygotes (p = 0.024, LSD-corrected), there was no linear association between number of minor/major alleles and age (p = 0.486).

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