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PR Timmers, N Mounier, K Lall, K Fischer, Z Ning, X Feng, AD Bretherick, DW Clark, M Agbessi, H Ahsan, I Alves, A Andiappan, P Awadalla, A Battle, MJ Bonder, D Boomsma, M Christiansen, A Claringbould, P Deelen, J van Dongen, T Esko, M Favé, L Franke, T Frayling, SA Gharib, G Gibson, G Hemani, R Jansen, A Kalnapenkis, S Kasela, J Kettunen, Y Kim, H Kirsten, P Kovacs, K Krohn, J Kronberg-Guzman, V Kukushkina, Z Kutalik, M Kähönen, B Lee, T Lehtimäki, M Loeffler, U Marigorta, A Metspalu, J van Meurs, L Milani, M Müller-Nurasyid, M Nauck, M Nivard, B Penninx, M Perola, N Pervjakova, B Pierce, J Powell, H Prokisch, BM Psaty, O Raitakari, S Ring, S Ripatti, O Rotzschke, S Ruëger, A Saha, M Scholz, K Schramm, I Seppälä, M Stumvoll, P Sullivan, A Teumer, J Thiery, L Tong, A Tönjes, J Verlouw, PM Visscher, U Võsa, U Völker, H Yaghootkar, J Yang, B Zeng, F Zhang, M Agbessi, H Ahsan, I Alves, A Andiappan, P Awadalla, A Battle, MJ Bonder, D Boomsma, M Christiansen, A Claringbould, P Deelen, J van Dongen, T Esko, M Favé, L Franke, T Frayling, SA Gharib, G Gibson, G Hemani, R Jansen, A Kalnapenkis, S Kasela, J Kettunen, Y Kim, H Kirsten, P Kovacs, K Krohn, J Kronberg-Guzman, V Kukushkina, Z Kutalik, M Kähönen, B Lee, T Lehtimäki, M Loeffler, U Marigorta, A Metspalu, J van Meurs, L Milani, M Müller-Nurasyid, M Nauck, M Nivard, B Penninx, M Perola, N Pervjakova, B Pierce, J Powell, H Prokisch, BM Psaty, O Raitakari, S Ring, S Ripatti, O Rotzschke, S Ruëger, A Saha, M Scholz, K Schramm, I Seppälä, M Stumvoll, P Sullivan, A Teumer, J Thiery, L Tong, A Tönjes, J Verlouw, PM Visscher, U Võsa, U Völker, H Yaghootkar, J Yang, B Zeng, F Zhang, X Shen, T Esko, Z Kutalik, JF Wilson and PK Joshi
Abstract
We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.
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