title: Complex variation in measures of general intelligence and cognitive change.
abstract: Combining information from multiple SNPs may capture a greater amount of genetic variation than from the sum of individual SNP effects and help identifying missing heritability. Regions may capture variation from multiple common variants of small effect, multiple rare variants or a combination of both. We describe regional heritability mapping of human cognition. Measures of crystallised (gc) and fluid intelligence (gf) in late adulthood (64-79 years) were available for 1806 individuals genotyped for 549,692 autosomal single nucleotide polymorphisms (SNPs). The same individuals were tested at age 11, enabling us the rare opportunity to measure cognitive change across most of their lifespan. 547,750 SNPs ranked by position are divided into 10, 908 overlapping regions of 101 SNPs to estimate the genetic variance each region explains, an approach that resembles classical linkage methods. We also estimate the genetic variation explained by individual autosomes and by SNPs within genes. Empirical significance thresholds are estimated separately for each trait from whole genome scans of 500 permutated data sets. The 5% significance threshold for the likelihood ratio test of a single region ranged from 17-17.5 for the three traits. This is the equivalent to nominal significance under the expectation of a chi-squared distribution (between 1 df and 0) of P<1.44×10(-5). These thresholds indicate that the distribution of the likelihood ratio test from this type of variance component analysis should be estimated empirically. Furthermore, we show that estimates of variation explained by these regions can be grossly overestimated. After applying permutation thresholds, a region for gf on chromosome 5 spanning the PRRC1 gene is significant at a genome-wide 10% empirical threshold. Analysis of gene methylation on the temporal cortex provides support for the association of PRRC1 and fluid intelligence (P = 0.004), and provides a prime candidate gene for high throughput sequencing of these uniquely informative cohorts.
authors.affiliation: The Roslin Institute, The University of Edinburgh, Roslin, Scotland, United Kingdom.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Rowe
authors.affiliation: The Roslin Institute, The University of Edinburgh, Roslin, Scotland, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Rowlatt
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: Gail
authors.initials: G
authors.lastname: Davies
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom ; Medical Genetics Section, The University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom ; Medical Genetics Section, The University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Liewald
authors.affiliation: Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: Geraldine
authors.initials: G
authors.lastname: McNeill
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom ; Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom ; Department of Psychology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: The Roslin Institute, The University of Edinburgh, Roslin, Scotland, United Kingdom ; Medical Research Council Human Genetics Unit at the Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
mesh_terms: D003071:Cognition / Q000502:physiology*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007360:Intelligence / Q000235:genetics / Q000502:physiology*; D016013:Likelihood Functions; D008297:Male; D008962:Models, Theoretical; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics