Exome sequencing to detect rare variants associated with general cognitive ability: a pilot study.
Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to individual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish individuals were selected for high scores on a general component of intelligence (g). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g. Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g. The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g. Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger samples would be worthwhile.
Centre for Cognitive Ageing and Cognitive Epidemiology,The University of Edinburgh,Edinburgh,UK.
Michelle
M
Luciano
MRC Human Genetics,Unit MRC IGMM,University of Edinburgh,Edinburgh,UK.
Victoria
V
Svinti
Medical Genetics Section,Centre for Genomic and Experimental Medicine,Institute of Genetics and Molecular Medicine,University of Edinburgh,Edinburgh,UK.
Archie
A
Campbell
Centre for Cognitive Ageing and Cognitive Epidemiology,The University of Edinburgh,Edinburgh,UK.
Riccardo E
RE
Marioni
MRC Human Genetics,Unit MRC IGMM,University of Edinburgh,Edinburgh,UK.
Caroline
C
Hayward
MRC Human Genetics,Unit MRC IGMM,University of Edinburgh,Edinburgh,UK.
Alan F
AF
Wright
MRC Human Genetics,Unit MRC IGMM,University of Edinburgh,Edinburgh,UK.
Martin S
MS
Taylor
Centre for Cognitive Ageing and Cognitive Epidemiology,The University of Edinburgh,Edinburgh,UK.
David J
DJ
Porteous
Centre for Cognitive Ageing and Cognitive Epidemiology,The University of Edinburgh,Edinburgh,UK.
Pippa
P
Thomson
MRC Human Genetics,Unit MRC IGMM,University of Edinburgh,Edinburgh,UK.
James G D
JG
Prendergast
MRC Human Genetics,Unit MRC IGMM,University of Edinburgh,Edinburgh,UK.
Nicholas D
ND
Hastie
MRC Human Genetics,Unit MRC IGMM,University of Edinburgh,Edinburgh,UK.
Susan M
SM
Farrington
A collaboration between the University Medical Schools and National Health Service in Aberdeen,Dundee,Edinburgh and Glasgow,UK.
Generation
G
Scotland
MRC Human Genetics,Unit MRC IGMM,University of Edinburgh,Edinburgh,UK.
Malcolm G
MG
Dunlop
Centre for Cognitive Ageing and Cognitive Epidemiology,The University of Edinburgh,Edinburgh,UK.
Ian J
IJ
Deary
D000328:Adult; D000368:Aged; D003071:Cognition; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007360:Intelligence / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D040641:Quantitative Trait Loci; D012606:Scotland
genetics