SORL1 is Genetically Associated with Neuropathologically Characterized Late-Onset Alzheimer's Disease

Abstract

SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [ = 0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE ε4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD.

Single Nucleotide Polymorphisms in Alzheimer’s Disease Risk Genes Are Associated with Intrinsic Connectivity in Middle Age

“…Our results extend these findings to demonstrate disrupted functional connectivity in resting state networks associated with memory and executive functioning. The current study also contributes to the mounting evidence in support of the relationships between SORL1 and AD-associated biomarkers [18, 72–74], although the literature on this specific topic is still somewhat equivocal [75, 76].…”

Single Nucleotide Polymorphisms in Alzheimer’s Disease Risk Genes Are Associated with Intrinsic Connectivity in Middle Age

“…Our results extend these findings to demonstrate disrupted functional connectivity in resting state networks associated with memory and executive functioning. The current study also contributes to the mounting evidence in support of the relationships between SORL1 and AD-associated biomarkers [18, 72–74], although the literature on this specific topic is still somewhat equivocal [75, 76].…”

Association between SORL1 polymorphisms and the risk of Alzheimer’s disease

“…Sensitivity analysis was carried out for each study to estimate the imputing value whether a single study has effect on the OR. When we excluding the study from Wen [23] under allele model, the heterogeneity decreased from P < 0.00001, I 2 = 92% to P = 0.46, I 2 = 0%. For other studies of this meta-analysis, no individual study affected the OR qualitatively, indicated that the studies brought into our meta-analysis were accurate.…”

“…After data extraction, 102 articles did not meet our inclusion criteria. Thus, 14 case-control studies involving 37941 cases and 49727 controls (updated in January 2017) were identified and classified for inclusion in the final meta-analysis (Lee et al [17], Cousin et al [11], Kimura et al [18], Feng et al [19], Shibata et al [20], Ning et al [21], Izzo et al [22], Wen et al [23], Ryan et al [24], Lee et al [25], Reynolds et al [26], Rowland et al [27], Lee et al [28] and Cellini et al [29]). All the compiled case-control studies were published from 2007 to 2017.…”

Elucidating Molecular Phenotypes Caused by the SORL1 Alzheimer’s Disease Genetic Risk Factor Using Human Induced Pluripotent Stem Cells

“…Multiple studies have confirmed a strong linkage disequilibrium in these regions using various population datasets (Bettens et al, 2008; Rogaeva et al, 2007; Wen et al, 2013). We genotyped our fibroblast lines for eight representative SORL1 variants, four SNPs in the 5′ region and four SNPs in the 3′ region.…”

Single Nucleotide Polymorphisms in Alzheimer’s Disease Risk Genes Are Associated with Intrinsic Connectivity in Middle Age

“…Our results extend these findings to demonstrate disrupted functional connectivity in resting state networks associated with memory and executive functioning. The current study also contributes to the mounting evidence in support of the relationships between SORL1 and AD-associated biomarkers [18, 72–74], although the literature on this specific topic is still somewhat equivocal [75, 76].…”

Association between SORL1 polymorphisms and the risk of Alzheimer’s disease

“…Sensitivity analysis was carried out for each study to estimate the imputing value whether a single study has effect on the OR. When we excluding the study from Wen [23] under allele model, the heterogeneity decreased from P < 0.00001, I 2 = 92% to P = 0.46, I 2 = 0%. For other studies of this meta-analysis, no individual study affected the OR qualitatively, indicated that the studies brought into our meta-analysis were accurate.…”

“…After data extraction, 102 articles did not meet our inclusion criteria. Thus, 14 case-control studies involving 37941 cases and 49727 controls (updated in January 2017) were identified and classified for inclusion in the final meta-analysis (Lee et al [17], Cousin et al [11], Kimura et al [18], Feng et al [19], Shibata et al [20], Ning et al [21], Izzo et al [22], Wen et al [23], Ryan et al [24], Lee et al [25], Reynolds et al [26], Rowland et al [27], Lee et al [28] and Cellini et al [29]). All the compiled case-control studies were published from 2007 to 2017.…”

Elucidating Molecular Phenotypes Caused by the SORL1 Alzheimer’s Disease Genetic Risk Factor Using Human Induced Pluripotent Stem Cells

“…Multiple studies have confirmed a strong linkage disequilibrium in these regions using various population datasets (Bettens et al, 2008; Rogaeva et al, 2007; Wen et al, 2013). We genotyped our fibroblast lines for eight representative SORL1 variants, four SNPs in the 5′ region and four SNPs in the 3′ region.…”

Single Nucleotide Polymorphisms in Alzheimer’s Disease Risk Genes Are Associated with Intrinsic Connectivity in Middle Age

“…Our results extend these findings to demonstrate disrupted functional connectivity in resting state networks associated with memory and executive functioning. The current study also contributes to the mounting evidence in support of the relationships between SORL1 and AD-associated biomarkers [18, 72–74], although the literature on this specific topic is still somewhat equivocal [75, 76].…”

Association between SORL1 polymorphisms and the risk of Alzheimer’s disease

“…Sensitivity analysis was carried out for each study to estimate the imputing value whether a single study has effect on the OR. When we excluding the study from Wen [23] under allele model, the heterogeneity decreased from P < 0.00001, I 2 = 92% to P = 0.46, I 2 = 0%. For other studies of this meta-analysis, no individual study affected the OR qualitatively, indicated that the studies brought into our meta-analysis were accurate.…”

“…After data extraction, 102 articles did not meet our inclusion criteria. Thus, 14 case-control studies involving 37941 cases and 49727 controls (updated in January 2017) were identified and classified for inclusion in the final meta-analysis (Lee et al [17], Cousin et al [11], Kimura et al [18], Feng et al [19], Shibata et al [20], Ning et al [21], Izzo et al [22], Wen et al [23], Ryan et al [24], Lee et al [25], Reynolds et al [26], Rowland et al [27], Lee et al [28] and Cellini et al [29]). All the compiled case-control studies were published from 2007 to 2017.…”

Elucidating Molecular Phenotypes Caused by the SORL1 Alzheimer’s Disease Genetic Risk Factor Using Human Induced Pluripotent Stem Cells

“…Multiple studies have confirmed a strong linkage disequilibrium in these regions using various population datasets (Bettens et al, 2008; Rogaeva et al, 2007; Wen et al, 2013). We genotyped our fibroblast lines for eight representative SORL1 variants, four SNPs in the 5′ region and four SNPs in the 3′ region.…”