title: Genome-wide association study of intelligence: additive effects of novel brain expressed genes.
abstract: OBJECTIVE
  The purpose of the present study was to identify common genetic variants that are associated with human intelligence or general cognitive ability.
  
  
  METHODS
  We performed a genome-wide association analysis with a dense set of 1 million single-nucleotide polymorphisms (SNPs) and quantitative intelligence scores within an ancestrally homogeneous family sample of 656 individuals with at least one child affected by attention-deficit/hyperactivity disorder (ADHD).
  
  
  RESULTS
  Haplotype trend regression analysis with sliding four-SNP windows identified haplotypes of genome-wide significance in genes involved in synaptic signaling (KIF16B; p = 1.27E-08) and neurodevelopment (PAX5; p = 3.58E-08), and highlight findings from a recent genetic study of cognitive ability (RXRA; p = 7.7E-08; GYPC; p = 2.5E-07). Further interrogation of SNPs within top haplotypes reveals that the minor alleles are associated with higher intelligence, whereas others are associated with relatively lower (but still average range) intelligence. Effects of the eight genes are additive, as a greater number of the associated genotypes in a given individual predict higher intelligence (p = 5.36E-08) and account for 8% of variance in intelligence.
  
  
  CONCLUSIONS
  Analyses that examine additive genetic effects may be useful in identifying regions where the additive effects of SNPs have a significant effect on phenotype. These results describe novel variants and additive effects of genes involved in brain development on variability in intelligence within an ADHD sample. The precise mechanisms of these loci in relation to determining individual differences in general cognitive ability require further investigation.
authors.affiliation: University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA. SLoo@mednet.ucla.edu
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Loo
authors.forename: Corina
authors.initials: C
authors.lastname: Shtir
authors.forename: Alysa E
authors.initials: AE
authors.lastname: Doyle
authors.forename: Eric
authors.initials: E
authors.lastname: Mick
authors.forename: James J
authors.initials: JJ
authors.lastname: McGough
authors.forename: James
authors.initials: J
authors.lastname: McCracken
authors.forename: Joseph
authors.initials: J
authors.lastname: Biederman
authors.forename: Susan L
authors.initials: SL
authors.lastname: Smalley
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
mesh_terms: D000293:Adolescent; D000483:Alleles; D001076:Aptitude / Q000502:physiology; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001921:Brain / Q000378:metabolism*; D002648:Child; D003071:Cognition / Q000502:physiology; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007360:Intelligence / Q000235:genetics*; D016547:Kinesins / Q000235:genetics; D008297:Male; D051757:PAX5 Transcription Factor / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C504670:KIF16B protein, human; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D016547:Kinesins