Gray matter heritability in family-based and population-based studies using voxel-based morphometry

Sven J van der Lee; Gennady V Roshchupkin; Hieab H H Adams; Helena Schmidt; Edith Hofer; Yasaman Saba; Reinhold Schmidt; Albert Hofman; Najaf Amin; Cornelia M van Duijn; Meike W Vernooij; M Arfan Ikram; Wiro J Niessen

doi:10.1002/hbm.23528

Gray matter heritability in family-based and population-based studies using voxel-based morphometry

Hum Brain Mapp. 2017 May;38(5):2408-2423. doi: 10.1002/hbm.23528. Epub 2017 Feb 1.

Authors

Sven J van der Lee¹, Gennady V Roshchupkin^{2

3}, Hieab H H Adams^{1

2}, Helena Schmidt^{4

5}, Edith Hofer^{6

7}, Yasaman Saba⁴, Reinhold Schmidt⁶, Albert Hofman¹, Najaf Amin¹, Cornelia M van Duijn¹, Meike W Vernooij^{1

2}, M Arfan Ikram^{1

2

8}, Wiro J Niessen^{2

3

9}

Affiliations

¹ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
² Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
³ Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
⁴ Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria.
⁵ Department of Neurology, Medical University Graz, Graz, Austria.
⁶ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, Graz, Austria.
⁷ Institute of Medical Informatics, Statistics and Documentation, Medical University Graz, Graz, Austria.
⁸ Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
⁹ Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands.

Abstract

Background: The combination of genetics and imaging has improved their understanding of the brain through studies of aggregate measures obtained from high-resolution structural imaging. Voxel-wise analyses have the potential to provide more detailed information of genetic influences on the brain. Here they report a large-scale study of the heritability of gray matter at voxel resolution (1 × 1 × 1 mm).

Methods: Validated voxel-based morphometry (VBM) protocols were applied to process magnetic resonance imaging data of 3,239 unrelated subjects from a population-based study and 491 subjects from two family-based studies. Genome-wide genetic data was used to estimate voxel-wise gray matter heritability of the unrelated subjects and pedigree-structure was used to estimate heritability in families. They subsequently associated two genetic variants, known to be linked with subcortical brain volume, with most heritable voxels to determine if this would enhance their association signals.

Results: Voxels significantly heritable in both estimates mapped to subcortical structures, but also voxels in the language areas of the left hemisphere were found significantly heritable. When comparing regional patterns of heritability, family-based estimates were higher than population-based estimates. However, regional consistency of the heritability measures across study designs was high (Pearson's correlation coefficient = 0.73, P = 2.6 × 10^-13 ). They further show enhancement of the association signal of two previously discovered genetic loci with subcortical volume by using only the most heritable voxels.

Conclusion: Gray matter voxel-wise heritability can be reliably estimated with different methods. Combining heritability estimates from multiple studies is feasible to construct reliable heritability maps of gray matter voxels. Hum Brain Mapp 38:2408-2423, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: brain structure heritability; family-based study; genetics; gray matter; magnetic resonance imaging; population-based study; voxel-based morphometry.

MeSH terms

Aged
Aged, 80 and over
Austria
Brain Mapping
Cohort Studies
Community Health Planning
Family Health*
Female
Genetic Linkage*
Gray Matter / diagnostic imaging*
Humans
Image Processing, Computer-Assisted
Magnetic Resonance Imaging*
Male
Middle Aged
Netherlands