Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Corpus callosum size is highly heritable in humans, and may reflect distinct genetic influences on ventral and rostral regions.

Anatomical differences in the corpus callosum have been found in various psychiatric disorders, but data on the genetic contributions to these differences have been limited. The current study used morphometric MRI data to assess the heritability of corpus callosum size and the genetic correlations among anatomical sub-regions of the corpus callosum among individuals with and without mood disorders. The corpus callosum (CC) was manually segmented at the mid-sagittal plane in 42 women (healthy, n = 14; major depressive disorder, n = 15; bipolar disorder, n = 13) and their 86 child or adolescent offspring. Four anatomical sub-regions (CC-genu, CC2, CC3 and CC-splenium) and total CC were measured and analyzed. Heritability and genetic correlations were estimated using a variance components method, with adjustment for age, sex, diagnosis, and diagnosis x age, where appropriate. Significant heritability was found for several CC sub-regions (P<0.01), with estimated values ranging from 48% (splenium) to 67% (total CC). There were strong and significant genetic correlations among most sub regions. Correlations between the genu and mid-body, between the genu and total corpus callosum, and between anterior and mid body were all >90%, but no significant genetic correlations were detected between ventral and rostral regions in this sample. Genetic factors play an important role in corpus callosum size among individuals. Distinct genetic factors seem to be involved in caudal and rostral regions, consistent with the divergent functional specialization of these brain areas

T1-weighted mid-sagittal view of the corpus callosum (CC).

<p>Six sub regions are shown: CC1 (genu), CC2, CC3, CC4, CC5 and CC6 (splenium).</p

Significance levels of covariates and corresponding beta coefficients, by sub-regions of the corpus callosum.

ns<p>P>0.05.</p

Stress Responsivity and HPA Axis Activity in Juveniles: Results From a Home-Based CO 2 Inhalation Study

Objective: A previous laboratory-based study found elevated cortisol levels in anxious children susceptible to CO 2 -induced panic, but the effects of parent diagnosis were not considered. The current home-based study tested the hypothesis that parental panic disorder and offspring response to CO 2 are associated with elevated cortisol levels in juvenile offspring. Method: A total of 131 offspring (ages 9–19) of parents with panic disorder, major depression, and no mental disorder underwent CO 2inhalation. Parent and child diagnoses were assessed. Salivary cortisol was assayed before and after CO2 inhalation. Results: Neither parents with panic disorder, parents with major depression, or offspring anxiety predicted offspring cortisol levels. Independent of parent and child diagnoses, anxiety response to CO 2 predicted elevated cortisol levels in offspring. Conclusions: As in adults, anxiety response to CO 2 in juveniles is associated with elevated cortisol levels, but elevated cortisol levels are not related to parent or child diagnoses

Heritability (diagonal) and Genetic Correlations (above diagonal)^a.

a<p>Mean and standard deviation.</p><p>**P≤0.01,</p><p>*P≤0.05.</p

Demographic data.

<p>Demographic data.</p