GWAS meta-analysis of cerebrospinal fluid Alzheimer's biomarkers reveals loci regulating lipids, brain volume and autophagy.
Timsina J., Jiang C., McCartney DL., Tao F., Dalmasso MC., Najar J., Anastasi F., Ohlei O., Puerta Fuentes R., Yang C., Bradley J., Western D., Ali M., Wang C., Yang C., Wu Y., Liu M., Budde J., Williams J., Mahoney R., Castillo Morales A., Hohman TJ., Dumitrescu L., Wang T-C., Tesi N., Kern S., Waern M., Skoog I., van Harten A., Pijnenburg YAL., van der Flier WM., 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., Düzel 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., Sánchez-Valle R., Álvarez V., García-González P., Mir P., Real LM., 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 MM., Lewczuk P., Kornhuber J., Hampel H., Giegling I., Goldhardt O., Diehl-Schmid J., Andrade V., Heneka MM., Frölich L., Vogelgsang J., Graff C., Thonberg H., Ullgren A., Papenberg G., Deleuze J-F., Dufouil C., Wagner M., Jessen F., Holstege H., van Duijn C., Lebouvier T., Hannon O., Leinonen V., Soininen H., Herukka S-K., Giedraitis V., Löwenmark M., Kilander L., Genius P., Rodríguez B., Luckett ES., Navarro A., Cano A., Marquié M., Blennow K., Zetterberg H., Lleo A., Boada M., Ruiz A., Lee VM-Y., Van Deerlin VM., Deming Y., Johnson SC., Engelman CD., Pastor P., Alvarez I., Peskind ER., Heslegrave AJ., Saykin AJ., Nho K., Schindler SE., Morris JC., Holtzman DM., McDade E., Renton AE., Goate A., Ibanez L., Riemenschneider M., Albert MS., Laws SM., Porter T., O'Brien EK., Shaw LM., Tijms BM., Ingelsson M., Visser PJ., Hiltunen M., Sleegers K., Ritchie CW., Sims R., Belloy M., Lambert J-C., Vilor-Tejedor N., Fernández MV., Li QS., Nagle MW., Marioni RE., Ramirez A., Bertram L., van der Lee SJ., Cruchaga C.
Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation.