{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:46:08Z","timestamp":1768567568047,"version":"3.49.0"},"posted":{"date-parts":[[2024,9,6]]},"group-title":"Genetic and Genomic Medicine","reference-count":132,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease (AD) has a high heritable component characteristic of complex diseases, yet many of the genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may be helpful to understand the underlying biology of the disease.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We performed a meta-analysis of GWAS of CSF A\u03b242 and PET measures combining six independent cohorts (n=2,076). Due to the opposite effect direction of A\u03b2 phenotypes in CSF and PET measures, only genetic signals in the opposite direction were considered for analysis (n=376,599). Polygenic risk scores (PRS) were calculated and evaluated for AD status and amyloid endophenotypes. We then searched the CSF proteome signature of brain amyloidosis using SOMAscan proteomic data (Ace cohort, n=1,008) and connected it with GWAS results of\n                    <jats:italic>loci<\/jats:italic>\n                    modulating amyloidosis. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n=13,409) and PET (n=13,116). This combined approach enabled the identification of overlapping genes and proteins associated with amyloid burden and the assessment of their biological significance using enrichment analyses.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-\n                    <jats:italic>APOE locus<\/jats:italic>\n                    and nine suggestive hits were annotated. We replicated the\n                    <jats:italic>APOE loci<\/jats:italic>\n                    using the large CSF-PET meta-GWAS and identified multiple AD-associated genes as well as the novel\n                    <jats:italic>GADL1<\/jats:italic>\n                    locus. Additionally, we found a significant association between the AD PRS and amyloid levels, whereas no significant association was found between any A\u03b2 PRS with AD risk. CSF SOMAscan analysis identified 1,387 FDR-significant proteins associated with CSF A\u03b242 levels. The overlap among GWAS\n                    <jats:italic>loci<\/jats:italic>\n                    and proteins associated with amyloid burden was very poor (n=35). The enrichment analysis of overlapping hits strongly suggested several signalling pathways connecting amyloidosis with the anchored component of the plasma membrane, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The strategy of combining CSF and PET amyloid endophenotypes GWAS with CSF proteome analyses might be effective for identifying signals associated with the AD pathological process and elucidate causative molecular mechanisms behind the amyloid mobilization in AD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.09.06.24313124","type":"posted-content","created":{"date-parts":[[2024,9,7]],"date-time":"2024-09-07T01:20:13Z","timestamp":1725672013000},"source":"Crossref","is-referenced-by-count":0,"title":["Connecting genomic and proteomic signatures 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