Common variants at 6q22 and 17q21 are associated with intracranial volume

Abstract

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study in 8,175 community-dwelling elderly did not reveal any genome-wide significant associations (p<5*10−8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (p=3.4*10−11), a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21 (p=1.5*10−12). We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 older persons (p=1.1*10−3 for 6q22 and p=1.2*10−3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age 14.5 months). Our data identify two loci associated with head size, with the inversion on 17q21 also likely involved in attaining maximal brain size.

Human adaptation and evolution by segmental duplication

“…Although the molecular basis for the selection of the European H2 locus is not known, it is interesting that the region contains several genes important in neural function, including MAPT —associated with several neurodegenerative disorders including Alzheimer’s disease, CRHR1 —a cortical-releasing hormone receptor, and KANSL1 —the gene responsible for the Koolen-de Vries syndrome [58]. It is interesting to note that the H2 haplotype was recently associated with increased intracranial volume indicating larger brain size [59]. …”

Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: Comparing meta and megaanalytical approaches for data pooling

“…One solution is collaborative data sharing and pooling through consortia such as Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium (http://enigma.ini.usc.edu). Recent examples highlight the potential of large, meta-analyses of genome-wide association studies (GWAS) to uncover genetic loci that are reliably and consistently associated with MRI-based phenotypes in worldwide datasets, including hippocampal volumes (Bis et al, 2012; Stein et al, 2012), intracranial volumes (Ikram et al, 2012; Stein et al, 2012), and head circumference (Taal et al, 2012). Recently, the ENIGMA-DTI Consortium working group was organized to develop methods to facilitate multi-site approaches to study genetic influences on white matter microarchitecture and integrity, assessed using diffusion tensor imaging (DTI).…”

Heritability of Subcortical and Limbic Brain Volume and Shape in Multiplex-Multigenerational Families with Schizophrenia

“…The recent identification of genetic variants that influence brain structure (1–3) is an important step in elucidating the biological mechanisms underlying neuropsychiatric disorders. Structural brain abnormalities are common in schizophrenia (4–6) and variation in regional brain volume is considered a putative endophenotype for the disorder (7–9).…”