Common Variants at 6q22 and 17q21 Are Associated with Intracranial Volume

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 (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (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-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 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 of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.

Citing Articles

Genomic structural equation modeling reveals latent phenotypes in the human cortex with distinct genetic architecture.

Morey R, Zheng Y, Bayly H, Sun D, Garrett M, Gasperi M Transl Psychiatry. 2024; 14(1):451.

PMID: 39448598 PMC: 11502831. DOI: 10.1038/s41398-024-03152-y.

Intracranial Volume Is Driven by Both Genetics and Early Life Exposures: The SOL-INCA-MRI Study.

Sofer T, Granot-Hershkovitz E, Tarraf W, Filigrana P, Isasi C, Suglia S Ethn Dis. 2024; 34(2):103-112.

PMID: 38973806 PMC: 11223032. DOI: 10.18865/ed.34.2.103.

Genetic relationship between the immune system and autism.

Arenella M, Fanelli G, Kiemeney L, McAlonan G, Murphy D, Bralten J Brain Behav Immun Health. 2023; 34:100698.

PMID: 38020478 PMC: 10663755. DOI: 10.1016/j.bbih.2023.100698.

The genetic relationships between brain structure and schizophrenia.

Stauffer E, Bethlehem R, Dorfschmidt L, Won H, Warrier V, Bullmore E Nat Commun. 2023; 14(1):7820.

PMID: 38016951 PMC: 10684873. DOI: 10.1038/s41467-023-43567-7.

Genomic Structural Equation Modeling Reveals Latent Phenotypes in the Human Cortex with Distinct Genetic Architecture.

Morey R, Zheng Y, Sun D, Garrett M, Gasperi M, Maihofer A Res Sq. 2023; .

PMID: 37886496 PMC: 10602057. DOI: 10.21203/rs.3.rs-3253035/v1.

References

Ikram M, Vrooman H, Vernooij M, van der Lijn F, Hofman A, van der Lugt A . Brain tissue volumes in the general elderly population. The Rotterdam Scan Study. Neurobiol Aging. 2007; 29(6):882-90. DOI: 10.1016/j.neurobiolaging.2006.12.012. View

Mortimer J, Snowdon D, Markesbery W . Head circumference, education and risk of dementia: findings from the Nun Study. J Clin Exp Neuropsychol. 2003; 25(5):671-9. DOI: 10.1076/jcen.25.5.671.14584. View

Gijselinck I, Van Broeckhoven C, Cruts M . Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update. Hum Mutat. 2008; 29(12):1373-86. DOI: 10.1002/humu.20785. View

DeCarli C, Massaro J, Harvey D, Hald J, Tullberg M, Au R . Measures of brain morphology and infarction in the framingham heart study: establishing what is normal. Neurobiol Aging. 2005; 26(4):491-510. DOI: 10.1016/j.neurobiolaging.2004.05.004. View

Zody M, Jiang Z, Fung H, Antonacci F, Hillier L, Cardone M . Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat Genet. 2009; 40(9):1076-83. PMC: 2684794. DOI: 10.1038/ng.193. View

Ikram M, Seshadri S, Bis J, Fornage M, DeStefano A, Aulchenko Y . Genomewide association studies of stroke. N Engl J Med. 2009; 360(17):1718-28. PMC: 2768348. DOI: 10.1056/NEJMoa0900094. View

Di Maria E, Cammarata S, Parodi M, Borghi R, Benussi L, Galli M . The H1 haplotype of the tau gene (MAPT) is associated with mild cognitive impairment. J Alzheimers Dis. 2010; 19(3):909-14. DOI: 10.3233/JAD-2010-1285. View

Atwood L, Wolf P, Heard-Costa N, Massaro J, Beiser A, DAgostino R . Genetic variation in white matter hyperintensity volume in the Framingham Study. Stroke. 2004; 35(7):1609-13. DOI: 10.1161/01.STR.0000129643.77045.10. View

Seshadri S, Fitzpatrick A, Ikram M, DeStefano A, Gudnason V, Boada M . Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010; 303(18):1832-40. PMC: 2989531. DOI: 10.1001/jama.2010.574. View

10.

von Rotz R, Kins S, Hipfel R, von der Kammer H, Nitsch R . The novel cytosolic RING finger protein dactylidin is up-regulated in brains of patients with Alzheimer's disease. Eur J Neurosci. 2005; 21(5):1289-98. DOI: 10.1111/j.1460-9568.2005.03977.x. View

11.

Donnelly M, Paschou P, Grigorenko E, Gurwitz D, Mehdi S, Kajuna S . The distribution and most recent common ancestor of the 17q21 inversion in humans. Am J Hum Genet. 2010; 86(2):161-71. PMC: 2820164. DOI: 10.1016/j.ajhg.2010.01.007. View

12.

Gijselinck I, van der Zee J, Engelborghs S, Goossens D, Peeters K, Mattheijssens M . Progranulin locus deletion in frontotemporal dementia. Hum Mutat. 2007; 29(1):53-8. DOI: 10.1002/humu.20651. View

13.

Gale C, OCallaghan F, Godfrey K, Law C, Martyn C . Critical periods of brain growth and cognitive function in children. Brain. 2003; 127(Pt 2):321-9. DOI: 10.1093/brain/awh034. View

14.

Gale C, OCallaghan F, Bredow M, Martyn C . The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years. Pediatrics. 2006; 118(4):1486-92. DOI: 10.1542/peds.2005-2629. View

15.

Koolen D, Sharp A, Hurst J, Firth H, Knight S, Goldenberg A . Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet. 2008; 45(11):710-20. PMC: 3071570. DOI: 10.1136/jmg.2008.058701. View

16.

Conrad C, Vianna C, Schultz C, Thal D, Ghebremedhin E, Lenz J . Molecular evolution and genetics of the Saitohin gene and tau haplotype in Alzheimer's disease and argyrophilic grain disease. J Neurochem. 2004; 89(1):179-88. DOI: 10.1046/j.1471-4159.2004.02320.x. View

17.

Psaty B, ODonnell C, Gudnason V, Lunetta K, Folsom A, Rotter J . Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ Cardiovasc Genet. 2009; 2(1):73-80. PMC: 2875693. DOI: 10.1161/CIRCGENETICS.108.829747. View

18.

Hsuchou H, Kastin A, Wu X, Tu H, Pan W . Corticotropin-releasing hormone receptor-1 in cerebral microvessels changes during development and influences urocortin transport across the blood-brain barrier. Endocrinology. 2009; 151(3):1221-7. PMC: 2840693. DOI: 10.1210/en.2009-1039. View

19.

Adams J, Tucker R . The thrombospondin type 1 repeat (TSR) superfamily: diverse proteins with related roles in neuronal development. Dev Dyn. 2000; 218(2):280-99. DOI: 10.1002/(SICI)1097-0177(200006)218:2<280::AID-DVDY4>3.0.CO;2-0. View

20.

Carmelli D, DeCarli C, Swan G, Jack L, Reed T, Wolf P . Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke. 1998; 29(6):1177-81. DOI: 10.1161/01.str.29.6.1177. View