Editors' ChoiceBrain Development

New genetic insights into brain size

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Science Translational Medicine  19 Oct 2016:
Vol. 8, Issue 361, pp. 361ec166
DOI: 10.1126/scitranslmed.aai9162

Abnormal intracranial volume has been associated with various human disorders. In the largest meta-analysis of genome-wide association (GWAS) data involving 32,438 adults, the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) and Heart and Aging Research in Genomic Epidemiology (CHARGE) consortia joined forces in studying the genetics of intracranial volume. These groups confirmed two known loci (6q22 and 17q21). Variants of the 6p22 locus are known to influence bone mineral density. The 17q21 locus contains multiple genes, including MAPT and KANSL1. While MAPT has been implicated in Parkinson’s disease, KANSL1 has been associated with intellectual disability. The authors also discovered five previously unknown loci (3q28, 6q21, 10q24, 12q14 and 12q23) for intracranial volume. Both 12q14 and 12q23 were found to be close to loci previously detected for head circumference in children (12q15 and 12q24). 3q28 is associated with genes responsible for DNA replication. 6q21 contains FOXO3, a gene responsible for regulating serum IGF1. Last, and importantly, 10q24 is where PDCD11 is located. PDCD11 encodes a nuclear factor κB–binding protein that is required for ribosomal RNA maturation and generation.

In addition to investigating intracranial volume of adults cross-sectionally, the authors also studied a longitudinal cohort of 2824 children followed prenatally until 6 years of age. They found that a higher polygenic score, representing a genetically larger intracranial volume in adults, was also associated with a larger child head circumference. They found significant associations between both 12q14 and 17q21 and child head circumference. The authors discovered that the G allele in the rs199525 variant at the 17q21 locus has a negative effect on head circumference postnatally, and this effect increased toward 6 years of age. In contrast, the G allele in the rs138074335 variant of the 12q14 locus exerted a positive effect on head circumference from early pregnancy to 1 year of age, but this effect became less prominent later in life.

Last, as expected, the authors revealed correlations between intracranial volume and cognitive function—both in childhood and adulthood. They also found an association between Parkinson’s disease and intracranial volume. However, their meta-analysis of intracranial volume involving adults did not reveal association with psychiatric traits.

H. H. H. Adams et al., Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nat. Neurosci. 0.1038/nn.4398 (2016). [Full Text]

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