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The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-ε4 carriers.

Benitez BA, Karch CM, Cai Y, Jin SC, Cooper B, Carrell D, Bertelsen S, Chibnik L, Schneider JA, Bennett DA, Alzheimer's Disease Neuroimaging InitiativeGenetic and Environmental Risk for Alzheimer's Disease Consortium GERADFagan AM, Holtzman D, Morris JC, Goate AM, Cruchaga C - PLoS Genet. (2013)

Bottom Line: Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2 × 10(-4)) and ptau (p = 1.8 × 10(-3)) levels.Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline.We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, School of Medicine, Washington University, St Louis, Missouri, United States of America.

ABSTRACT
The primary constituents of plaques (Aβ42/Aβ40) and neurofibrillary tangles (tau and phosphorylated forms of tau [ptau]) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF Aβ42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2 × 10(-4)) and ptau (p = 1.8 × 10(-3)) levels. The association of the p.E318G variant with Aβ deposition was observed in APOE-ε4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-ε4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7-24.6) that is similar to APOE-ε4 homozygous (OR = 9.9, 95% CI = 7.2.9-13.6), and double the risk for APOE-ε4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4-4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition.

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Distribution of PSEN1 p.E318G mutation carriers in CSF Biomarker quartiles.A. CSF tau, Logistic regression model p = 6.0×10−4. B. CSF pTau, Logistic regression model p = 3.0×10−4. C. CSF Aβ42, Logistic regression model p = 0.38. White bars represent the number of non carriers. Black bars represent the number of carriers D. Association of PSEN1 gene with CSF tau. E. Association of PSEN1 gene with CSF ptau. F. Association of PSEN1 gene with CSF Aβ42. Plots are showing the most significant SNP at a given locus along with the combined-analysis results for SNPs in the region surrounding it (typically ±500 kb). Symbols are colored according to the LD of the SNP with the top SNP (r2 color-based insert). The red line represents the threshold for significance. The light blue line represents the estimated recombination rate. G. LD Block for the most significant SNP associated with biomarker levels at PSEN1 genomic region: SNP rs76342307 based on the 1000 genome project for Europeans. Gene annotations are shown as dark green lines. H. LD Block for rs76342307 and rs17125721 in our own data set. I. Plot after the conditional analysis including both SNPs (rs76342307 and rs17125721) in the model.
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pgen-1003685-g001: Distribution of PSEN1 p.E318G mutation carriers in CSF Biomarker quartiles.A. CSF tau, Logistic regression model p = 6.0×10−4. B. CSF pTau, Logistic regression model p = 3.0×10−4. C. CSF Aβ42, Logistic regression model p = 0.38. White bars represent the number of non carriers. Black bars represent the number of carriers D. Association of PSEN1 gene with CSF tau. E. Association of PSEN1 gene with CSF ptau. F. Association of PSEN1 gene with CSF Aβ42. Plots are showing the most significant SNP at a given locus along with the combined-analysis results for SNPs in the region surrounding it (typically ±500 kb). Symbols are colored according to the LD of the SNP with the top SNP (r2 color-based insert). The red line represents the threshold for significance. The light blue line represents the estimated recombination rate. G. LD Block for the most significant SNP associated with biomarker levels at PSEN1 genomic region: SNP rs76342307 based on the 1000 genome project for Europeans. Gene annotations are shown as dark green lines. H. LD Block for rs76342307 and rs17125721 in our own data set. I. Plot after the conditional analysis including both SNPs (rs76342307 and rs17125721) in the model.

Mentions: Next, we tested whether any of the variants identified by an endophenotype-based approach could improve our understanding of both the genetic architecture and pathophysiology of LOAD [17], [18]. We ran a linear regression analysis for single SNP using CSF biomarkers as quantitative traits, but we failed to find significant association with CSF tau, ptau or Aβ42 levels for most of the identified variants, even after we collapsed all of the potentially damaging variants in each gene and analyzed the dataset for carriers vs. non-carriers of these variants (Table 3). Surprisingly, a low frequency coding variant in PSEN1, p.E318G (rs17125721) (MAF = 0.02 for Europeans Americans, Exome Variant Server EVS: http://evs.gs.washington.edu/EVS/), whose pathogenic role is currently debated [34] exhibited a statistically significant association (multiple test correction threshold, p = 7.0×10−3) with CSF tau (p = 9.2×10−4, Beta = 0.14) and ptau levels (P = 1.8×10−3, Beta = 0.12), but not with Aβ42 (p = 0.14, Beta = −0.05). Interestingly, it has been reported that the combination of Aβ42 and tau or ptau as a ratio provides the best discriminative value to date for AD cases [35], [36] and predict the conversion from non-dementia clinical status to dementia [37]. p.E318G exhibited a significant association with the ratio of ptau∶Aβ42 (p = 9.5×10−5, Beta = 0.08) and tau∶Aβ42 (p = 2.0×10−4, Beta = 0.06) (Figure 1A–C, 2A) suggesting that the association of p.E318G with CSF biomarker levels may be an association with clinical AD.


The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-ε4 carriers.

Benitez BA, Karch CM, Cai Y, Jin SC, Cooper B, Carrell D, Bertelsen S, Chibnik L, Schneider JA, Bennett DA, Alzheimer's Disease Neuroimaging InitiativeGenetic and Environmental Risk for Alzheimer's Disease Consortium GERADFagan AM, Holtzman D, Morris JC, Goate AM, Cruchaga C - PLoS Genet. (2013)

Distribution of PSEN1 p.E318G mutation carriers in CSF Biomarker quartiles.A. CSF tau, Logistic regression model p = 6.0×10−4. B. CSF pTau, Logistic regression model p = 3.0×10−4. C. CSF Aβ42, Logistic regression model p = 0.38. White bars represent the number of non carriers. Black bars represent the number of carriers D. Association of PSEN1 gene with CSF tau. E. Association of PSEN1 gene with CSF ptau. F. Association of PSEN1 gene with CSF Aβ42. Plots are showing the most significant SNP at a given locus along with the combined-analysis results for SNPs in the region surrounding it (typically ±500 kb). Symbols are colored according to the LD of the SNP with the top SNP (r2 color-based insert). The red line represents the threshold for significance. The light blue line represents the estimated recombination rate. G. LD Block for the most significant SNP associated with biomarker levels at PSEN1 genomic region: SNP rs76342307 based on the 1000 genome project for Europeans. Gene annotations are shown as dark green lines. H. LD Block for rs76342307 and rs17125721 in our own data set. I. Plot after the conditional analysis including both SNPs (rs76342307 and rs17125721) in the model.
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Related In: Results  -  Collection

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pgen-1003685-g001: Distribution of PSEN1 p.E318G mutation carriers in CSF Biomarker quartiles.A. CSF tau, Logistic regression model p = 6.0×10−4. B. CSF pTau, Logistic regression model p = 3.0×10−4. C. CSF Aβ42, Logistic regression model p = 0.38. White bars represent the number of non carriers. Black bars represent the number of carriers D. Association of PSEN1 gene with CSF tau. E. Association of PSEN1 gene with CSF ptau. F. Association of PSEN1 gene with CSF Aβ42. Plots are showing the most significant SNP at a given locus along with the combined-analysis results for SNPs in the region surrounding it (typically ±500 kb). Symbols are colored according to the LD of the SNP with the top SNP (r2 color-based insert). The red line represents the threshold for significance. The light blue line represents the estimated recombination rate. G. LD Block for the most significant SNP associated with biomarker levels at PSEN1 genomic region: SNP rs76342307 based on the 1000 genome project for Europeans. Gene annotations are shown as dark green lines. H. LD Block for rs76342307 and rs17125721 in our own data set. I. Plot after the conditional analysis including both SNPs (rs76342307 and rs17125721) in the model.
Mentions: Next, we tested whether any of the variants identified by an endophenotype-based approach could improve our understanding of both the genetic architecture and pathophysiology of LOAD [17], [18]. We ran a linear regression analysis for single SNP using CSF biomarkers as quantitative traits, but we failed to find significant association with CSF tau, ptau or Aβ42 levels for most of the identified variants, even after we collapsed all of the potentially damaging variants in each gene and analyzed the dataset for carriers vs. non-carriers of these variants (Table 3). Surprisingly, a low frequency coding variant in PSEN1, p.E318G (rs17125721) (MAF = 0.02 for Europeans Americans, Exome Variant Server EVS: http://evs.gs.washington.edu/EVS/), whose pathogenic role is currently debated [34] exhibited a statistically significant association (multiple test correction threshold, p = 7.0×10−3) with CSF tau (p = 9.2×10−4, Beta = 0.14) and ptau levels (P = 1.8×10−3, Beta = 0.12), but not with Aβ42 (p = 0.14, Beta = −0.05). Interestingly, it has been reported that the combination of Aβ42 and tau or ptau as a ratio provides the best discriminative value to date for AD cases [35], [36] and predict the conversion from non-dementia clinical status to dementia [37]. p.E318G exhibited a significant association with the ratio of ptau∶Aβ42 (p = 9.5×10−5, Beta = 0.08) and tau∶Aβ42 (p = 2.0×10−4, Beta = 0.06) (Figure 1A–C, 2A) suggesting that the association of p.E318G with CSF biomarker levels may be an association with clinical AD.

Bottom Line: Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2 × 10(-4)) and ptau (p = 1.8 × 10(-3)) levels.Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline.We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, School of Medicine, Washington University, St Louis, Missouri, United States of America.

ABSTRACT
The primary constituents of plaques (Aβ42/Aβ40) and neurofibrillary tangles (tau and phosphorylated forms of tau [ptau]) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF Aβ42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2 × 10(-4)) and ptau (p = 1.8 × 10(-3)) levels. The association of the p.E318G variant with Aβ deposition was observed in APOE-ε4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-ε4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7-24.6) that is similar to APOE-ε4 homozygous (OR = 9.9, 95% CI = 7.2.9-13.6), and double the risk for APOE-ε4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4-4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition.

Show MeSH
Related in: MedlinePlus