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Title | One for all and all for One: Improving replication of genetic studies through network diffusion. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Lancour D, Naj A, Mayeux R, Haines JL, Pericak-Vance MA, Schellenberg GD, Crovella M, Farrer LA, Kasif S |
Journal | PLoS Genet |
Volume | 14 |
Issue | 4 |
Pagination | e1007306 |
Date Published | 2018 04 |
ISSN | 1553-7404 |
Keywords | Alzheimer Disease, Datasets as Topic, Genome-Wide Association Study, Humans, Protein Interaction Maps, Reproducibility of Results, Risk Factors, Support Vector Machine |
Abstract | Improving accuracy in genetic studies would greatly accelerate understanding the genetic basis of complex diseases. One approach to achieve such an improvement for risk variants identified by the genome wide association study (GWAS) approach is to incorporate previously known biology when screening variants across the genome. We developed a simple approach for improving the prioritization of candidate disease genes that incorporates a network diffusion of scores from known disease genes using a protein network and a novel integration with GWAS risk scores, and tested this approach on a large Alzheimer disease (AD) GWAS dataset. Using a statistical bootstrap approach, we cross-validated the method and for the first time showed that a network approach improves the expected replication rates in GWAS studies. Several novel AD genes were predicted including CR2, SHARPIN, and PTPN2. Our re-prioritized results are enriched for established known AD-associated biological pathways including inflammation, immune response, and metabolism, whereas standard non-prioritized results were not. Our findings support a strategy of considering network information when investigating genetic risk factors. |
DOI | 10.1371/journal.pgen.1007306 |
Alternate Journal | PLoS Genet. |
PubMed ID | 29684019 |
PubMed Central ID | PMC5933817 |
Grant List | P50 AG005138 / NH / NIH HHS / United States U24 AG21886 / NH / NIH HHS / United States P01 AG019724 / NH / NIH HHS / United States P01 AG03991 / NH / NIH HHS / United States R01 AG15819 / NH / NIH HHS / United States P50 AG008702 / NH / NIH HHS / United States P30 AG012300 / NH / NIH HHS / United States P50 AG005133 / NH / NIH HHS / United States P30 AG010129 / NH / NIH HHS / United States 5R01AG012101 / NH / NIH HHS / United States AG02365 / NH / NIH HHS / United States P50 AG005681 / NH / NIH HHS / United States AG030653 / NH / NIH HHS / United States U01 AG032984 / NH / NIH HHS / United States 1R01AG035137 / NH / NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States P30 AG019610 / NH / NIH HHS / United States P30 AG008017 / NH / NIH HHS / United States P50 AG005136 / NH / NIH HHS / United States R01 NS059873 / NH / NIH HHS / United States P50 AG016582 / NH / NIH HHS / United States P50 AG016573 / NH / NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States U24-AG041689-01 / NH / NIH HHS / United States UO1 HG006375 / NH / NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States RC2 AG036528 / NH / NIH HHS / United States R01 AG017173 / NH / NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States UO1 AG006781 / NH / NIH HHS / United States P50 AG008671 / NH / NIH HHS / United States U01 AG016976 / NH / NIH HHS / United States P30 AG013846 / NH / NIH HHS / United States 5R01AG022374 / NH / NIH HHS / United States P50 AG023501 / NH / NIH HHS / United States AG021547 / NH / NIH HHS / United States AG041718 / NH / NIH HHS / United States P50 AG005142 / NH / NIH HHS / United States AG010491 / NH / NIH HHS / United States R01 AG027944 / NH / NIH HHS / United States R01 CA129769 / NH / NIH HHS / United States AG05144 / NH / NIH HHS / United States R01 AG30146 / NH / NIH HHS / United States P30 AG013854 / NH / NIH HHS / United States R01 AG17917 / NH / NIH HHS / United States P30 AG010161 / NH / NIH HHS / United States AG07562 / NH / NIH HHS / United States R37 AG015473 / NH / NIH HHS / United States R01 AG031581 / NH / NIH HHS / United States R01 AG025259 / NH / NIH HHS / United States UO1 HG004610 / NH / NIH HHS / United States P30 AG10133 / NH / NIH HHS / United States P30 AG010124 / NH / NIH HHS / United States AG025688 / NH / NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States T32 GM100842 / GM / NIGMS NIH HHS / United States R01 MH080295 / NH / NIH HHS / United States AG027944 / NH / NIH HHS / United States R01 AG048927 / NH / NIH HHS / United States U24 AG026395 / NH / NIH HHS / United States R01AG33193 / NH / NIH HHS / United States P01 AG002219 / NH / NIH HHS / United States AG05128 / NH / NIH HHS / United States R01 AG026916 / NH / NIH HHS / United States U01 AG10483 / NH / NIH HHS / United States P50 AG033514 / NH / NIH HHS / United States R01 AG019085 / NH / NIH HHS / United States P50 AG005134 / NH / NIH HHS / United States P30 AG028383 / NH / NIH HHS / United States R01AG041797 / NH / NIH HHS / United States P50 AG005131 / NH / NIH HHS / United States P30 AG08051 / NH / NIH HHS / United States UL1 RR029893 / NH / NIH HHS / United States P50 AG005146 / NH / NIH HHS / United States 1RC2AG036502 / NH / NIH HHS / United States R01 AG020688 / NH / NIH HHS / United States 5R01AG013616 / NH / NIH HHS / United States P30 AG028377 / NH / NIH HHS / United States P50 AG016574 / NH / NIH HHS / United States AG019757 / NH / NIH HHS / United States P50 AG016570 / NH / NIH HHS / United States |