GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy.
Cruchaga C., Timsina J., Jiang C., McCartney D., Tao F., Dalmasso MC., Najar J., Anastasi F., Ohlei O., Puerta R., Bradley J., Western D., Ali M., Wang C., Yang C., Wu Y., Liu M., Budde J., Williams J., Mahoney R., Castillo A., Hohman T., Dumitrescu L., Wang T-C., Tesi N., Kern S., Waern M., Skoog I., van Harten A., van der Flier W., Sánchez-Juan P., Rodriguez-Rodriguez E., Kleineidam L., Peters O., Schneider A., Küçükali F., Bellenguez C., Grenier-Boley B., Heikkinen S., de Rojas I., Rujescu D., Scherbaum N., Hausner L., Duzel E., Grimmer T., Wiltfang J., Vandenberghe R., Engelborghs S., Heilmann-Heimbach S., Schmid M., Tegos T., Scarmeas N., Dols-Icardo O., Moreno F., Pérez-Tur J., Bullido MJ., Sanchez-Valle R., Álvarez V., Garcia-Gonzalez P., Mir P., Real L., Piñol-Ripoll G., García-Alberca JM., Seelaar H., Ramakers I., Papma J., Hulsman M., Laske C., Teipel S., Priller J., Perneczky R., Buerger K., Nöthen M., Lewczuk P., Kornhuber J., Maier W., Hampel H., Giegling I., Goldhardt O., Diehl-Schmid J., Andrade V., Heneka M., Froelich L., Vogelgsang J., Graff C., Thonberg H., Ullgren A., Papenberg G., Boland A., Deleuze J-F., Wagner M., Jessen F., Holstege H., van Duijn C., Lebouvier T., Hanon O., Leinonen V., Soininen H., Herukka S-K., Giedraitis V., Löwenmark M., Kilander L., Genius P., Rodríguez B., Luckett E., Navarro A., Cano A., Marquié M., Blennow K., Zetterberg H., Lleo A., Boada M., Laza AR., Lee V., Deerlin VV., Deming Y., Johnson S., Engelman C., Pastor P., Alvarez I., Peskind E., Heslegrave A., Saykin A., Nho K., Schindler S., Morris J., Holtzman D., McDade E., Renton A., Goate A., Ibanez L., Riemenschneider M., Albert M., Laws S., Porter T., O'Brien E., Shaw L., Tijms B., Ingelsson M., Visser PJ., Hiltunen M., Sleegers K., Ritchie C., Sims R., Lambert J-C., Vilor-Tejedor N., Fernández M., Li Q., Nagle M., Marioni R., Ramirez A., Bertram L., van der Lee S.
Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation.