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Heritability of Hippocampal Formation Sub-region Volumes

Kiefer S Greenspan, Claire R Arakelian and Theo GM Van Erp

Background: Hippocampal formation (HF) volume and episodic memory performance are substantially heritable, but HF sub-region heritability estimates and their possible shared genetic variance with episodic memory performance remain to be determined.

Methods and findings: This study provides heritability estimates for hippocampal sub-regions (e.g. Cornu Amonis, Subiculum, Parasubiculum, Molecular and Granule Cell Layers of the Dentate Gryus) and Total HF volumes obtained using FreeSurfer 6.0. In addition, this study assesses the heritability of object sequence and verbal episodic memory performance, and the amount of shared genetic variance between HF sub-regions and Total HF volume and episodic memory performance. HF volumes were obtained from high-resolution brain scans from a sample of 499 siblings (mean age ± SD=30.0 ± 3.1, 203 men), including 51 monozygotic and 46 dizygotic twin pairs and 305 non-twin siblings, collected by the Human Connectome Project (www.humanconnectome.org). Heritability estimates for HF sub-regions ranged from 0.42-0.87 and shared genetic variance of HF sub-regions with hippocampal volume was substantial (mean=0.79, range=0.50-0.98). HF sub-region volumes residualized for Total HF and percent HF sub-region volumes were also found to be substantially heritable (range=0.04-0.86 and 0.07-0.84, respectively). Verbal (h2=0.47) but not object sequence episodic memory was found to be significantly heritable; though the amount of shared genetic variance between HF sub-regions and verbal episodic memory was low (mean=0.10, range=0.01-0.20).

Conclusion: These findings suggest that HF sub-region volumes are heritable and can be used as quantitative phenotypes in genetic association studies. The low shared genetic variance between HF sub-regions and verbal episodic memory suggests that quantitative trait analyses may not benefit from including both HF volume and episodic memory as bivariate traits in healthy individuals. The extent to which HF sub-region volumes share genetic variance with neuropsychiatric disorders, and as such add value to our ability to identify genetic risk loci for these disorders, remains to be determined.