Three Novel Loci for Infant Head Circumference Identified by a Joint Association Analysis

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.

Patterns of Fetal and Infant Growth and Brain Morphology at Age 10 Years

“…54 Previous studies have found that the genetic background of birth weight is also associated with head circumference at birth and in later life. 55,56 Altogether, the findings of the current study suggest that fetal and infant weight growth are associated with brain morphology in school-age children. Even though the observed associations are relatively small, they are important from a developmental and preventive perspective.…”

High heritability of ascending aortic diameter and multi-ethnic prediction of thoracic aortic disease.

“…AsAoD displayed a high heritability in line with other continuous measurements of human anatomy such as height and head circumference 34 . However, genetic determinants of the aortic outflow tract size are likely under purifying selection as comparative anatomy suggests the physiological demands of cardiac output are relatively invariant across a wide range of mammalian body sizes 35 .…”

“…These findings suggest a shared genetic architecture between AsAoD and cardiovascular diseases and risk factors.Our gene level association studies identified 147 trait associations among which 19 genes were also found to be significantly enriched in multiple tissues and cell types including heart, blood vessels, and cells transformed fibroblast; highlighting a potential role of these genes in functions related to development, maintenance, or regulation of aorta structure and diameter. This finding is concordant with our tissue enrichment analysis that showed significant enrichment of GWAS signals in the aorta, arteries, heart and other predominantly smooth muscle cell tissues.AsAoD displayed a high heritability in line with other continuous measurements of human anatomy such as height and head circumference34 . However, genetic determinants of the aortic outflow tract size are likely under purifying selection as comparative anatomy suggests the physiological demands of cardiac output are relatively invariant across a wide range of mammalian body sizes35 .…”

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium

“…Both rs17361324 (ADCY5) and rs215226 (B4GALNT3) have enhancer and promoter histone marks and eQTLs in the respective genes in relevant tissues. For BMI, there is an eQTL for rs17361324-ADCY5 in thyroid, and ADCY5 has been previously associated with type 2 diabetes, 91 BMI, 92 central obesity traits, 43 height, 51 birth outcomes, [93][94][95] and a number of other phenotypes. Additionally, rs17361324 is proximate to an ADCY5 intronic variant (rs1093467, r²=0.3 in 1000 Genomes AMR) that is highly conserved across species (Haploreg v4.1).…”