TY - JOUR
T1 - Transcript levels in plasma contribute substantial predictive value as potential Alzheimer's disease biomarkers in African Americans
AU - Reddy, Joseph S.
AU - Jin, Jiangli
AU - Lincoln, Sarah J.
AU - Ho, Charlotte C.G.
AU - Crook, Julia E.
AU - Wang, Xue
AU - Malphrus, Kimberly G.
AU - Nguyen, Thuy
AU - Tamvaka, Nikoleta
AU - Greig-Custo, Maria T.
AU - Lucas, John A.
AU - Graff-Radford, Neill R.
AU - Ertekin-Taner, Nilüfer
AU - Carrasquillo, Minerva M.
N1 - Funding Information:
We thank the participants and their families for their participation in research. Without them this work would not have been possible. We are also thankful to the Mayo Clinic Memory Disorders Center Coordinators including Michelle Fudge, Rita Fletcher, Francine Parfitt, Kelly Smith, and Sylvia Grant. We also thank the Mayo Clinic Center for Health Equity and Community Engagement Research for their support. This work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].
Funding Information:
We thank the participants and their families for their participation in research. Without them this work would not have been possible. We are also thankful to the Mayo Clinic Memory Disorders Center Coordinators including Michelle Fudge, Rita Fletcher, Francine Parfitt, Kelly Smith, and Sylvia Grant. We also thank the Mayo Clinic Center for Health Equity and Community Engagement Research for their support. This work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/4
Y1 - 2022/4
N2 - Background: African Americans (AA) remain underrepresented in Alzheimer's disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer's Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. Method: Utilizing FCA3DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. Findings: Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. Receiver operating characteristic analysis of age, sex APOE-ε4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% area under the curve to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-ε4 dosage. Interpretation: Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. Funding: This work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].
AB - Background: African Americans (AA) remain underrepresented in Alzheimer's disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer's Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. Method: Utilizing FCA3DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. Findings: Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. Receiver operating characteristic analysis of age, sex APOE-ε4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% area under the curve to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-ε4 dosage. Interpretation: Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. Funding: This work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].
KW - African Americans
KW - Alzheimer's disease
KW - Biomarkers
KW - Gene expression
KW - Plasma
KW - Whole exome sequencing
KW - cf-mRNA
KW - eQTL
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U2 - 10.1016/j.ebiom.2022.103929
DO - 10.1016/j.ebiom.2022.103929
M3 - Article
C2 - 35307406
AN - SCOPUS:85128330425
VL - 78
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
M1 - 103929
ER -