ABSTRACT
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.
Subject(s)
Cognition Disorders/genetics , Cognition/physiology , Genetic Predisposition to Disease/genetics , HMGN1 Protein/genetics , Polymorphism, Single Nucleotide/genetics , Aged , Aged, 80 and over , Atherosclerosis/complications , Cognition Disorders/etiology , Cohort Studies , Female , Genome-Wide Association Study , Humans , Male , Middle Aged , Neuropsychological Tests , Phenotype , ScotlandABSTRACT
The toxicity of smoke from cigarettes containing tobacco, Cytrel tobacco supplement, or mixtures of the 2 materials, was investigated using 6 short term test methods. The tests used were rat trachea organ culture and mouse skin thickening tests, which may provide information on carcinogenicity, a ciliatoxicity test, an alveolar macrophage viability test, a haemolysis assay and a thiol inactivation test to provide measures of irritant and cytotoxic effects. In each case a response to the smoke from cigarettes containing tobacco alone was detected, while the magnitude of this response declined as the proportion of tobacco supplement in the blend increased. The least response was found with smoke from cigarettes containing Cytrel tobacco supplement alone.
Subject(s)
Cellulose/analogs & derivatives , Smoking/pathology , Trachea/pathology , Animals , Cellulose/toxicity , Cilia/drug effects , Epidermis/drug effects , Hemolysis/drug effects , Macrophages/ultrastructure , Organ Culture Techniques , Pulmonary Alveoli/pathology , Rats , Sulfhydryl Compounds/metabolismSubject(s)
Nicotiana , Plants, Toxic , Tars/toxicity , Animals , Carcinogens , Humans , Mice , MutagensABSTRACT
Membranes of dead fetuses showed a three-fold increase in permeability to the haemoglobin molecule when compared with normal and stored membranes. The friability of some of these membranes was markedly increased and their strength and elasticity diminished. These findings may be significant in the aetiology of the hypofibrinogenaemia and the increased incidence of amniotic fluid embolism with intrauterine death of the fetus.