%0 Journal Article %J Neurol Genet %D 2017 %T The Alzheimer's Disease Sequencing Project: Study design and sample selection. %A Beecham, Gary W %A Bis, J C %A Martin, E R %A Choi, S-H %A DeStefano, A L %A van Duijn, C M %A Fornage, M %A Gabriel, S B %A Koboldt, D C %A Larson, D E %A Naj, A C %A Psaty, B M %A Salerno, W %A Bush, W S %A Foroud, T M %A Wijsman, E %A Farrer, L A %A Goate, A %A Haines, J L %A Pericak-Vance, Margaret A %A Boerwinkle, E %A Mayeux, R %A Seshadri, S %A Schellenberg, G %B Neurol Genet %V 3 %P e194 %8 2017 Oct %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29184913?dopt=Abstract %R 10.1212/NXG.0000000000000194 %0 Journal Article %J Mol Psychiatry %D 2015 %T Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). %A Davies, G %A Armstrong, N %A Bis, J C %A Bressler, J %A Chouraki, V %A Giddaluru, S %A Hofer, E %A Ibrahim-Verbaas, C A %A Kirin, M %A Lahti, J %A van der Lee, S J %A Le Hellard, S %A Liu, T %A Marioni, R E %A Oldmeadow, C %A Postmus, I %A Smith, A V %A Smith, J A %A Thalamuthu, A %A Thomson, R %A Vitart, V %A Wang, J %A Yu, L %A Zgaga, L %A Zhao, W %A Boxall, R %A Harris, S E %A Hill, W D %A Liewald, D C %A Luciano, M %A Adams, H %A Ames, D %A Amin, N %A Amouyel, P %A Assareh, A A %A Au, R %A Becker, J T %A Beiser, A %A Berr, C %A Bertram, L %A Boerwinkle, E %A Buckley, B M %A Campbell, H %A Corley, J %A De Jager, P L %A Dufouil, C %A Eriksson, J G %A Espeseth, T %A Faul, J D %A Ford, I %A Gottesman, R F %A Griswold, M E %A Gudnason, V %A Harris, T B %A Heiss, G %A Hofman, A %A Holliday, E G %A Huffman, J %A Kardia, S L R %A Kochan, N %A Knopman, D S %A Kwok, J B %A Lambert, J-C %A Lee, T %A Li, G %A Li, S-C %A Loitfelder, M %A Lopez, O L %A Lundervold, A J %A Lundqvist, A %A Mather, K A %A Mirza, S S %A Nyberg, L %A Oostra, B A %A Palotie, A %A Papenberg, G %A Pattie, A %A Petrovic, K %A Polasek, O %A Psaty, B M %A Redmond, P %A Reppermund, S %A Rotter, J I %A Schmidt, H %A Schuur, M %A Schofield, P W %A Scott, R J %A Steen, V M %A Stott, D J %A van Swieten, J C %A Taylor, K D %A Trollor, J %A Trompet, S %A Uitterlinden, A G %A Weinstein, G %A Widen, E %A Windham, B G %A Jukema, J W %A Wright, A F %A Wright, M J %A Yang, Q %A Amieva, H %A Attia, J R %A Bennett, D A %A Brodaty, H %A de Craen, A J M %A Hayward, C %A Ikram, M A %A Lindenberger, U %A Nilsson, L-G %A Porteous, D J %A Räikkönen, K %A Reinvang, I %A Rudan, I %A Sachdev, P S %A Schmidt, R %A Schofield, P R %A Srikanth, V %A Starr, J M %A Turner, S T %A Weir, D R %A Wilson, J F %A van Duijn, C %A Launer, L %A Fitzpatrick, A L %A Seshadri, S %A Mosley, T H %A Deary, I J %K Aged %K Aged, 80 and over %K Atherosclerosis %K Cognition %K Cognition Disorders %K Cohort Studies %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K HMGN1 Protein %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Scotland %X

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

%B Mol Psychiatry %V 20 %P 183-92 %8 2015 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract %R 10.1038/mp.2014.188