Abstract
As an important trait at birth, infant head circumference (HC) is associated with a variety of intelligence- and mental-related conditions. Despite being dominated by genetics, the mechanism underlying the variation of HC is poorly understood. Aiming to uncover the genetic basis of HC, we performed a genome-wide joint association analysis by integrating the genome-wide association summary statistics of HC with that of its two related traits, birth length and birth weight, using a recently developed integrative method, multitrait analysis of genome-wide association (MTAG), and performed in silico replication in an independent sample of intracranial volume (N = 26,577). We then conducted a series of bioinformatic investigations on the identified loci. Combining the evidence from both the MTAG analysis and the in silico replication, we identified three novel loci at the genome-wide significance level (α = 5.0 × 10−8): 3q23 [lead single nucleotide polymorphism (SNP) rs9846396, p MTAG = 3.35 × 10−8, p replication = 0.01], 7p15.3 (rs12534093, p MTAG = 2.00 × 10−8, p replication = 0.004), and 9q33.3 (rs7048271 p MTAG = 9.23 × 10−10, p replication = 1.14 × 10−4). Each of the three lead SNPs was associated with at least one of eight brain-related traits including intelligence and educational attainment. Credible risk variants, defined as those SNPs located within 500 kb of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in DNase I hypersensitive site region in brain. Nine candidate genes were prioritized at the three novel loci using multiple sources of information. Gene set enrichment analysis identified one associated pathway GO:0048009, which participates in the development of nervous system. Our findings provide useful insights into the genetic basis of HC and the relationship between brain growth and mental health.
Highlights
The size of infant head circumference (HC) is thought to affect brain development in later life (Ivanovic et al, 2004)
All genome-wide association study (GWAS) meta-analyses for the three individual traits were carried out by the Early Growth Genetics (EGG) consortium, and basic characteristics of individual studies are detailed in respective publications (Table 1) (Taal et al, 2012; van der Valk et al, 2015; Horikoshi et al, 2016)
After excluding the two lead single nucleotide polymorphism (SNP) and their neighboring SNPs within 500 kb to either direction, the heritability is 0.22 (s.e. = 0.04), showing that most of the SNPattributable heritability is hidden in the current GWAS setting
Summary
The size of infant head circumference (HC) is thought to affect brain development in later life (Ivanovic et al, 2004) It is associated with a variety of intelligence- and mental-related conditions, such as intelligence quotient (IQ) score (Ivanovic et al, 2004), autism (Aylward et al, 2002), and Alzheimer’s disease (Schofield et al, 1997). Many studies attempt to define some conceptual growth parameters by integrating the three traits to comprehensively reflect children’s health status (Sankilampi et al, 2013; Haksari et al, 2016) Their high phenotypic correlation (Scheffler et al, 2017) implies that these traits may share some common genetic architecture. We will perform gene set enrichment analysis to highlight relevant pathways
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