Childhood intelligence is heritable, highly polygenic and associated with FNBP1L

Abstract

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6–18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22–46% of phenotypic variation in childhood intelligence in the three largest cohorts (P = 3.9 × 10−15, 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P = 0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P = 6 × 10−5), 3.5% (P = 10−3) and 0.5% (P = 6 × 10−5) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait

“…Despite the high heritability of intelligence, 12,28,37,38 the progress in the identification of loci consistently associated with variation in its normal range has thus far been limited. 15,17,[38][39][40][41][42] Exceptions are the apolipoprotein E (APOE) gene at older ages 43 and formin binding protein 1-like (FNBP1L), the latter having recently been shown to be associated with both childhood and adulthood intelligence. 15,17 The present approach utilizes the idea that the differentially sized effects of individual mutations located within a gene functionally relevant to the phenotype may range from severe disruptions of protein functioning (resulting in a Mendelian disorder) to smaller effects underlying polygenic variation.…”

“…15,17,[38][39][40][41][42] Exceptions are the apolipoprotein E (APOE) gene at older ages 43 and formin binding protein 1-like (FNBP1L), the latter having recently been shown to be associated with both childhood and adulthood intelligence. 15,17 The present approach utilizes the idea that the differentially sized effects of individual mutations located within a gene functionally relevant to the phenotype may range from severe disruptions of protein functioning (resulting in a Mendelian disorder) to smaller effects underlying polygenic variation. Utilizing prior knowledge on genetics of Mendelian disorders may therefore prove a valuable approach to the identification of genetic variability underlying polygenic traits, with the advantage of requiring considerably smaller sample sizes than GWAS to achieve adequate power.…”

“…[13][14][15][16] The two largest genome-wide association studies (GWAS) to date failed to find replicable genome-wide association in SNP-based analyses in adults and children, respectively. 15,17 The 43 genes considered in the present study are a subset of the genes identified in a recent study that used homozygosity mapping, exon enrichment, and next-generation sequencing in consanguineous families with autosomal-recessive intellectual disabilities to identify single, presumably disease-causing variants in 50 novel candidate genes. 11 The genome-wide data set of the Netherlands Twin Register (NTR), 18 used in the present study, contains SNP data on 43 of these 50 genes (Table 1), including 1227 genotyped SNPs in total (Supplementary Table S1).…”

Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood

“…High heritability has been observed in twin‐based studies for various neurocognitive traits, including episodic memory, working memory and general cognitive ability [Ando J et al, 2001; Haworth et al, 2010; Owens SF et al, 2011]. Similarly, molecular genetic studies have predicted increased heritability estimates for general cognitive ability in the general population by considering the additive effects of thousands common genetic markers in the human genome [Plomin R et al, 2013; Benyamin B et al, 2014]. Due to the close relationship between neurocognitive deficits and psychiatric illness, nationwide collaborative efforts have joined forces in order to investigate the potential contribution of common genetic variation to neurocognitive performance, which may also lead to the identification of specific genetic loci involved in psychiatric nosology [Donohoe G et al, 2013; Lencz T et al, 2014].…”

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

“…First, variation in genetic architecture has been associated with the intelligence quotient (IQ) distribution itself. Although IQ overall is highly heritable (21)(22)(23)(24), there is evidence that severe intellectual disabilities, which exist at the low tail of the Significance Autism spectrum disorder (ASD) research is complicated by heterogeneity. There are several types of genetic risk factors for ASDs, and that diversity may be reflected in case presentation.…”