TY - JOUR
T1 - Influence of Genetic Variation on Plasma Protein Levels in Older Adults Using a Multi-Analyte Panel
AU - Kim, Sungeun
AU - Swaminathan, Shanker
AU - Inlow, Mark
AU - Risacher, Shannon L.
AU - Nho, Kwangsik
AU - Shen, Li
AU - Foroud, Tatiana M.
AU - Petersen, Ronald C.
AU - Aisen, Paul S.
AU - Soares, Holly
AU - Toledo, Jon B.
AU - Shaw, Leslie M.
AU - Trojanowski, John Q.
AU - Weiner, Michael W.
AU - McDonald, Brenna C.
AU - Farlow, Martin R.
AU - Ghetti, Bernardino
AU - Saykin, Andrew J.
N1 - Funding Information:
ADNI is funded in part through generous contributions from the following: Abbott; Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. However, no funding from any commercial source, listed in the paper, was directly received by the authors. Co-author Holly Soares is employed by Bristol Myers Squibb Co. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.
PY - 2013/7/23
Y1 - 2013/7/23
N2 - Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology. Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Linear regression analysis detected 112 significant (Bonferroni threshold p = 2.44×10-5) associations between 27 analytes and 112 SNPs. 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p<0.05 in the same direction of effect as those in the ADNI. We identified multiple novel associations including the association of rs7517126 with plasma complement factor H-related protein 1 (CFHR1) level at p<1.46×10-60, accounting for 40 percent of total variation of the protein level. We serendipitously found the association of rs6677604 with the same protein at p<9.29×10-112. Although these two SNPs were not in the strong linkage disequilibrium, 61 percent of total variation of CFHR1 was accounted for by rs6677604 without additional variation by rs7517126 when both SNPs were tested together. 78 other SNP-protein associations in the ADNI sample exceeded genome-wide significance (5×10-8). Our results confirmed previously identified gene-protein associations for interleukin-6 receptor, chemokine CC-4, angiotensin-converting enzyme, and angiotensinogen, although the direction of effect was reversed in some cases. This study is among the first analyses of gene-protein product relationships integrating multiplex-panel proteomics and targeted genes extracted from a GWAS array. With intensive searches taking place for proteomic biomarkers for many diseases, the role of genetic variation takes on new importance and should be considered in interpretation of proteomic results.
AB - Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology. Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Linear regression analysis detected 112 significant (Bonferroni threshold p = 2.44×10-5) associations between 27 analytes and 112 SNPs. 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p<0.05 in the same direction of effect as those in the ADNI. We identified multiple novel associations including the association of rs7517126 with plasma complement factor H-related protein 1 (CFHR1) level at p<1.46×10-60, accounting for 40 percent of total variation of the protein level. We serendipitously found the association of rs6677604 with the same protein at p<9.29×10-112. Although these two SNPs were not in the strong linkage disequilibrium, 61 percent of total variation of CFHR1 was accounted for by rs6677604 without additional variation by rs7517126 when both SNPs were tested together. 78 other SNP-protein associations in the ADNI sample exceeded genome-wide significance (5×10-8). Our results confirmed previously identified gene-protein associations for interleukin-6 receptor, chemokine CC-4, angiotensin-converting enzyme, and angiotensinogen, although the direction of effect was reversed in some cases. This study is among the first analyses of gene-protein product relationships integrating multiplex-panel proteomics and targeted genes extracted from a GWAS array. With intensive searches taking place for proteomic biomarkers for many diseases, the role of genetic variation takes on new importance and should be considered in interpretation of proteomic results.
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U2 - 10.1371/journal.pone.0070269
DO - 10.1371/journal.pone.0070269
M3 - Article
C2 - 23894628
AN - SCOPUS:84880709736
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 7
M1 - e70269
ER -