Genetics of microstructure of cerebral white matter using diffusion tensor imaging.

Adult; Aged; Aged, 80 and over; Anisotropy; Brain Mapping; Cerebral Cortex/anatomy & histology; Diffusion Tensor Imaging; Female; Humans; Image Interpretation, Computer-Assisted; Male; Middle Aged; Quantitative Trait Loci; Quantitative Trait, Heritable; Young Adult

Abstract :

[en] We analyzed the degree of genetic control over intersubject variability in the microstructure of cerebral white matter (WM) using diffusion tensor imaging (DTI). We performed heritability, genetic correlation and quantitative trait loci (QTL) analyses for the whole-brain and 10 major cerebral WM tracts. Average measurements for fractional anisotropy (FA), radial (L( perpendicular)) and axial (L( vertical line)) diffusivities served as quantitative traits. These analyses were done in 467 healthy individuals (182 males/285 females; average age 47.9+/-13.5 years; age range: 19-85 years), recruited from randomly-ascertained pedigrees of extended families. Significant heritability was observed for FA (h(2)=0.52+/-0.11; p=10(-7)) and L( perpendicular) (h(2)=0.37+/-0.14; p=0.001), while L( vertical line) measurements were not significantly heritable (h(2)=0.09+/-0.12; p=0.20). Genetic correlation analysis indicated that the FA and L( perpendicular) shared 46% of the genetic variance. Tract-wise analysis revealed a regionally diverse pattern of genetic control, which was unrelated to ontogenic factors, such as tract-wise age-of-peak FA values and rates of age-related change in FA. QTL analysis indicated linkages for whole-brain average FA (LOD=2.36) at the marker D15S816 on chromosome 15q25, and for L( perpendicular) (LOD=2.24) near the marker D3S1754 on the chromosome 3q27. These sites have been reported to have significant co-inheritance with two psychiatric disorders (major depression and obsessive-compulsive disorder) in which patients show characteristic alterations in cerebral WM. Our findings suggest that the microstructure of cerebral white matter is under a strong genetic control and further studies in healthy as well as patients with brain-related illnesses are imperative to identify the genes that may influence cerebral white matter.

Disciplines :

Anatomy (cytology, histology, embryology...) & physiology

Author, co-author :

Kochunov, P.

Glahn, D. C.

Lancaster, J. L.

Winkler, Anderson ; Université de Liège - ULiège > Form. doc. sc. bioméd. & pharma.

Smith, S.

Thompson, P. M.

Almasy, L.

Duggirala, R.

Fox, P. T.

Blangero, J.

Language :

English

Title :

Genetics of microstructure of cerebral white matter using diffusion tensor imaging.

Publication date :

2010

Journal title :

NeuroImage

ISSN :

1053-8119

eISSN :

1095-9572

Publisher :

Elsevier, Amsterdam, Netherlands

Volume :

Issue :

Pages :

1109-16

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 03 May 2017

Statistics

Number of views

56 (0 by ULiège)

Number of downloads

109 (0 by ULiège)

More statistics

Scopus citations^®

149

Scopus citations^®
without self-citations

105

OpenCitations

127

OpenAlex citations

157

Bibliography

Abe O., Aoki S., Hayashi N., Yamada H., Kunimatsu A., Mori H., Yoshikawa T., Okubo T., Ohtomo K. Normal aging in the central nervous system: quantitative MR diffusion-tensor analysis. Neurobiol. Aging 2002, 23:433-441.
Aboitiz F. Brain connections: interhemispheric fiber systems and anatomical brain asymmetries in humans. Biol. Res. 1992, 25:51-61.
Aboitiz F., Scheibel A.B., Fisher R.S., Zaidel E. Fiber composition of the human corpus callosum. Brain. Res. 1992, 598:143-153.
Almasy L., Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am. J. Hum. Genet. 1998, 62:1198-1211.
Almasy L., Dyer T., Blangero J. Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages. Genet. Epidemiol. 1997, 14:953-958.
Almasy L., Dyer T.D., Blangero J. Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages. Genet. Epidemiol. 1997, 14:953-958.
Amos C., de Andrade M., Zhu D. Comparison of multivariate tests for genetic linkage. Hum. Hered. 2001, 51:133-144.
Amos C.I., Laing A.E. A comparison of univariate and multivariate tests for genetic linkage. Genet. Epidemiol. 1993, 10:671-676.
Basser P.J. Focal magnetic stimulation of an axon. IEEE Trans. Biomed. Eng. 1994, 41:601-606.
Basser P.J. Inferring microstructural features and the physiological state of tissues from diffusion-weighted images. NMR Biomed. 1995, 8:333-344.
Basser P.J., Mattiello J., LeBihan D. MR diffusion tensor spectroscopy and imaging. Biophys. J. 1994, 66:259-267.
Beaulieu C. The basis of anisotropic water diffusion in the nervous system-a technical review. NMR Biomed. 2002, 15:435-455.
Behrens T.E., Woolrich M.W., Jenkinson M., Johansen-Berg H., Nunes R.G., Clare S., Matthews P.M., Brady J.M., Smith S.M. Characterization and propagation of uncertainty in diffusion-weighted MR imaging. Magn. Reson. Med. 2003, 50:1077-1088.
Boehnke M. Allele frequency estimation from data on relatives. Am. J. Hum. Genet. 1991, 48:22-25.
Brun C., Lepore N., Pennec X., Chou Y.Y., Lee A.D., Barysheva M., de Zubicaray G., Meredith M., McMahon K., Wright M.J., Toga A.W., Thompson P.M. A tensor-based morphometry study of genetic influences on brain structure using a new fluid registration method. Med. Image. Comput. Comput. Assist. Interv. Int. Conf. Med. Image. Comput. Comput. Assist. Interv. 2008, 11:914-921.
Budde M.D., Kim J.H., Liang H.F., Schmidt R.E., Russell J.H., Cross A.H., Song S.K. Toward accurate diagnosis of white matter pathology using diffusion tensor imaging. Magn. Reson. Med. 2007, 57:688-695.
Cheverud J.M., Falk D., Vannier M., Konigsberg L., Helmkamp R.C., Hildebolt C. Heritability of brain size and surface features in rhesus macaques (Macaca mulatta). J. Hered. 1990, 81:51-57.
Chiang M.C., Leow A.D., Klunder A.D., Dutton R.A., Barysheva M., Rose S.E., McMahon K.L., de Zubicaray G.I., Toga A.W., Thompson P.M. Fluid registration of diffusion tensor images using information theory. IEEE Trans. Med. Imaging. 2008, 27:442-456.
Chiang M.C., Barysheva M., Shattuck D.W., Lee A.D., Madsen S.K., Avedissian C., Klunder A.D., Toga A.W., McMahon K.L., de Zubicaray G.I., Wright M.J., Srivastava A., Balov N., Thompson P.M. Genetics of brain fiber architecture and intellectual performance. J. Neurosci. 2009, 29:2212-2224.
Chiang M., Avedissian C., Barysheva M., Toga A., McMahon K., de Zubicaray G., Wright M., Thompson P. Extending genetic linkage analysis to diffusion tensor images to map single gene effects on brain fiber architecture. Med. Image Comput. Comput. Assist. Interv. 2009, 5762:506-513.
Choquette A.C., Lemieux S., Tremblay A., Chagnon Y.C., Bouchard C., Vohl M.C., Perusse L. Evidence of a quantitative trait locus for energy and macronutrient intakes on chromosome 3q27.3: the Quebec Family Study. Am. J. Clin. Nutr. 2008, 88:1142-1148.
Conturo T.E., McKinstry R.C., Akbudak E., Robinson B.H. Encoding of anisotropic diffusion with tetrahedral gradients: a general mathematical diffusion formalism and experimental results. Magn. Reson. Med. 1996, 35:399-412.
Crick F., Jones E. Backwardness of human neuroanatomy. Nature 1993, 361:109-110.
DeStefano A.L., Atwood L.D., Massaro J.M., Heard-Costa N., Beiser A., Au R., Wolf P.A., DeCarli C. Genome-wide scan for white matter hyperintensity: the Framingham Heart Study. Stroke 2006, 37:77-81.
Gao W., Lin W., Chen Y., Gerig G., Smith J.K., Jewells V., Gilmore J.H. Temporal and spatial development of axonal maturation and myelination of white matter in the developing brain. AJNR Am. J. Neuroradiol. 2009, 30:290-296.
Gogtay N., Giedd J.N., Lusk L., Hayashi K.M., Greenstein D., Vaituzis A.C., Nugent T.F., Herman D.H., Clasen L.S., Toga A.W., Rapoport J.L., Thompson P.M. Dynamic mapping of human cortical development during childhood through early adulthood. Proc. Natl. Acad. Sci. U. S. A. 2004, 101:8174-8179.
Goring H.H., Curran J.E., Johnson M.P., Dyer T.D., Charlesworth J., Cole S.A., Jowett J.B., Abraham L.J., Rainwater D.L., Comuzzie A.G., Mahaney M.C., Almasy L., MacCluer J.W., Kissebah A.H., Collier G.R., Moses E.K., Blangero J. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat. Genet. 2007, 39:1208-1216.
Heath S.C. Markov chain Monte Carlo segregation and linkage analysis for oligogenic models. Am. J. Hum. Genet. 1997, 61:748-760.
Hoeft F., Barnea-Goraly N., Haas B.W., Golarai G., Ng D., Mills D., Korenberg J., Bellugi U., Galaburda A., Reiss A.L. More is not always better: increased fractional anisotropy of superior longitudinal fasciculus associated with poor visuospatial abilities in Williams syndrome. J. Neurosci. 2007, 27:11960-11965.
Holmans P., Zubenko G.S., Crowe R.R., DePaulo J.R., Scheftner W.A., Weissman M.M., Zubenko W.N., Boutelle S., Murphy-Eberenz K., MacKinnon D., McInnis M.G., Marta D.H., Adams P., Knowles J.A., Gladis M., Thomas J., Chellis J., Miller E., Levinson D.F. Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q. Am. J. Hum. Genet. 2004, 74:1154-1167.
Hulshoff Pol H.E., Schnack H.G., Posthuma D., Mandl R.C., Baare W.F., van Oel C., van Haren N.E., Collins D.L., Evans A.C., Amunts K., Burgel U., Zilles K., de Geus E., Boomsma D.I., Kahn R.S. Genetic contributions to human brain morphology and intelligence. J. Neurosci. 2006, 26:10235-10242.
Jones D.K., Horsfield M.A., Simmons A. Optimal strategies for measuring diffusion in anisotropic systems by magnetic resonance imaging. Magn. Reson. Med. 1999, 42:515-525.
Kammerer C.M., Schneider J.L., Cole S.A., Hixson J.E., Samollow P.B., O'Connell J.R., Perez R., Dyer T.D., Almasy L., Blangero J., Bauer R.L., Mitchell B.D. Quantitative trait loci on chromosomes 2p, 4p, and 13q influence bone mineral density of the forearm and hip in Mexican Americans. J. Bone Miner. Res. 2003, 18:2245-2252.
Klein A., Andersson J., Ardekani B.A., Ashburner J., Avants B., Chiang M.C., Christensen G.E., Collins D.L., Gee J., Hellier P., Song J.H., Jenkinson M., Lepage C., Rueckert D., Thompson P., Vercauteren T., Woods R.P., Mann J.J., Parsey R.V. Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. NeuroImage 2009, 46:786-802.
Kochunov P., Lancaster J.L., Thompson P., Woods R., Mazziotta J., Hardies J., Fox P. Regional spatial normalization: toward an optimal target. J. Comput. Assist. Tomogr. 2001, 25:805-816.
Kochunov P., Thompson P.M., Lancaster J.L., Bartzokis G., Smith S., Coyle T., Royall D.R., Laird A., Fox P.T. Relationship between white matter fractional anisotropy and other indices of cerebral health in normal aging: tract-based spatial statistics study of aging. Neuroimage 2007, 35:478-487.
Kochunov P., Glahn D., Winkler A., Duggirala R., Olvera R., Cole S.A., Dyer T.D., Almasy L., Fox P., Blangero J. Analysis of genetic variability and whole genome linkage of whole-brain, subcortical and ependymal hyperintense white matter volume. Stroke 2009, 40:3685-3690.
Kochunov P., Glahn D., Fox P.T., Lancaster J., Saleem K., Shelledy W., Zilles K., Thompson P., Coulon O., Blangero J., Fox P., J., R. Genetics of primary cerebral gyrification: Heritability of length, depth and area of primary sulci in an extended pedigree of Papio baboons. Neuroimage 2010, 53:1124-1132.
Kochunov P., Williamson D., Lancaster J., Fox P., Cornell J., Blangero J., Glahn D. Fractional anisotropy of water diffusion in cerebral white matter across the lifespan. Neurobiol. Aging 2010, 30:1149-1155.
Kong A., Gudbjartsson D.F., Sainz J., Jonsdottir G.M., Gudjonsson S.A., Richardsson B., Sigurdardottir S., Barnard J., Hallbeck B., Masson G., Shlien A., Palsson S.T., Frigge M.L., Thorgeirsson T.E., Gulcher J.R., Stefansson K. A high-resolution recombination map of the human genome. Nat. Genet. 2002, 31:241-247.
Konrad A., Vucurevic G., Musso F., Stoeter P., Dahmen N., Winterer G. ErbB4 genotype predicts left frontotemporal structural connectivity in human brain. Neuropsychopharmacology 2009, 34:641-650.
Le Bihan D. Looking into the functional architecture of the brain with diffusion MRI. Nat. Rev. Neurosci. 2003, 4:469-480.
Lee, A.D., Lepore, N., Barysheva, M., Yi-Yu Chou Brun, C., Madsen, S.K., McMahon, K.L., de Zubicaray, G.I., Meredith, M., Wright, M.J., Toga, A.W., Thompson, P., 2008. Comparison of fractional and geodesic anisotropy in diffusion tensor images of 90 monozygotic and dizygotic twins. Biomedical Imaging: From Nano to Macro, 2008. ISBI 2008. 5th IEEE International Symposium. pp 943-946.
Lohmann G., von Cramon D.Y., Steinmetz H. Sulcal variability of twins. Cereb. Cortex 1999, 9:754-763.
Madler B., Drabycz S.A., Kolind S.H., Whittall K.P., MacKay A.L. Is diffusion anisotropy an accurate monitor of myelination? Correlation of multicomponent T2 relaxation and diffusion tensor anisotropy in human brain. Magn. Reson. Imaging 2008, 26:874-888.
Marenco S., Siuta M.A., Kippenhan J.S., Grodofsky S., Chang W.L., Kohn P., Mervis C.B., Morris C.A., Weinberger D.R., Meyer-Lindenberg A., Pierpaoli C., Berman K.F. Genetic contributions to white matter architecture revealed by diffusion tensor imaging in Williams syndrome. Proc. Natl. Acad. Sci. U. S. A. 2007, 104:15117-15122.
McAuley E.Z., Blair I.P., Liu Z., Fullerton J.M., Scimone A., Van Herten M., Evans M.R., Kirkby K.C., Donald J.A., Mitchell P.B., Schofield P.R. A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26. Mol. Psychiatry 2009, 14:492-500.
McIntosh A.M., Moorhead T.W., Job D., Lymer G.K., Munoz Maniega S., McKirdy J., Sussmann J.E., Baig B.J., Bastin M.E., Porteous D., Evans K.L., Johnstone E.C., Lawrie S.M., Hall J. The effects of a neuregulin 1 variant on white matter density and integrity. Mol. Psychiatry 2008, 13:1054-1059.
Mitchell B.D., Kammerer C.M., Blangero J., Mahaney M.C., Rainwater D.L., Dyke B., Hixson J.E., Henkel R.D., Sharp R.M., Comuzzie A.G., VandeBerg J.L., Stern M.P., MacCluer J.W. Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study. Circulation 1996, 94:2159-2170.
Niesler B., Frank B., Kapeller J., Rappold G.A. Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E. Gene 2003, 310:101-111.
Park N., Juo S.H., Cheng R., Liu J., Loth J.E., Lilliston B., Nee J., Grunn A., Kanyas K., Lerer B., Endicott J., Gilliam T.C., Baron M. Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia. Mol. Psychiatry 2004, 9:1091-1099.
Pfefferbaum A., Sullivan E.V., Hedehus M., Lim K.O., Adalsteinsson E., Moseley M. Age-related decline in brain white matter anisotropy measured with spatially corrected echo-planar diffusion tensor imaging. Magn. Reson. Med. 2000, 44:259-268.
Pierpaoli C., Basser P.J. Toward a quantitative assessment of diffusion anisotropy. Magn. Reson. Med. 1996, 36:893-906.
Raff M. Neural development: mysterious no more. Science 1996, 274:1063.
Schmithorst V.J., Holland S.K., Dardzinski B.J. Developmental differences in white matter architecture between boys and girls. Hum. Brain. Mapp. 2008, 29:696-710.
Shugart Y.Y., Samuels J., Willour V.L., Grados M.A., Greenberg B.D., Knowles J.A., McCracken J.T., Rauch S.L., Murphy D.L., Wang Y., Pinto A., Fyer A.J., Piacentini J., Pauls D.L., Cullen B., Page J., Rasmussen S.A., Bienvenu O.J., Hoehn-Saric R., Valle D., Liang K.Y., Riddle M.A., Nestadt G. Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol. Psychiatry 2006, 11:763-770.
Smith S., Jenkinson M., Woolrich M., Beckmann C., Behrens T., Johansen-Berg H., Bannister P., De Luca M., Drobnjak I., Flitney D., Niazy R., Saunders J., Vickers J., Zhang Y., De Stefano N., Brady J., Matthews P. Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 2004, 23:208-219.
Smith SM Fast robust automated brain extraction. Hum. Brain Mapp. 2002, 17:143-155.
Smith S.M., Jenkinson M., Johansen-Berg H., Rueckert D., Nichols T.E., Mackay C.E., Watkins K.E., Ciccarelli O., Cader M.Z., Matthews P.M., Behrens T.E. Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. NeuroImage 2006, 31:1487-1505.
Smith S.M., Jenkinson M., Johansen-Berg H., Rueckert D., Nichols T.E., Mackay C.E., Watkins K.E., Ciccarelli O., Cader M.Z., Matthews P.M., Behrens T.E. Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. Neuroimage 2006, 31(4):1487-1505.
Smith S.M., Johansen-Berg H., Jenkinson M., Rueckert D., Nichols T.E., Miller K.L., Robson M.D., Jones D.K., Klein J.C., Bartsch A.J., Behrens T.E. Acquisition and voxelwise analysis of multi-subject diffusion data with tract-based spatial statistics. Nat. Protoc. 2007, 2:499-503.
Sobel E., Lange K. Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am. J. Hum. Genet. 1996, 58:1323-1337.
Song S.K., Sun S.W., Ju W.K., Lin S.J., Cross A.H., Neufeld A.H. Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 2003, 20:1714-1722.
Song S.K., Yoshino J., Le T.Q., Lin S.J., Sun S.W., Cross A.H., Armstrong R.C. Demyelination increases radial diffusivity in corpus callosum of mouse brain. NeuroImage 2005, 26:132-140.
Sullivan E.V., Adalsteinsson E., Hedehus M., Ju C., Moseley M., Lim K.O., Pfefferbaum A. Equivalent disruption of regional white matter microstructure in ageing healthy men and women. NeuroReport 2001, 12:99-104.
Sutton B.S., Weinert S., Langefeld C.D., Williams A.H., Campbell J.K., Saad M.F., Haffner S.M., Norris J.M., Bowden D.W. Genetic analysis of adiponectin and obesity in Hispanic families: the IRAS Family Study. Hum. Genet. 2005, 117:107-118.
Turner S.T., Fornage M., Jack C.R., Mosley T.H., Kardia S.L., Boerwinkle E., de Andrade M. Genomic susceptibility loci for brain atrophy in hypertensive sibships from the GENOA study. Hypertension 2005, 45:793-798.
Ulug A.M., Barker P.B., van Zijl P.C. Correction of motional artifacts in diffusion-weighted images using a reference phase map. Magn. Reson. Med. 1995, 34:476-480.
Wakana S., Jiang H., Nagae-Poetscher L.M., van Zijl P.C., Mori S. Fiber tract-based atlas of human white matter anatomy. Radiology 2004, 230:77-87.
Westerhausen R., Kreuder F., Dos Santos Sequeira S., Walter C., Woerner W., Wittling R.A., Schweiger E., Wittling W. Effects of handedness and gender on macro-and microstructure of the corpus callosum and its subregions: a combined high-resolution and diffusion-tensor MRI study. Brain Res. Cogn. Brain Res. 2004, 21:418-426.
Williams-Hogarth L.C., Puche A.C., Torrey C., Cai X., Song I., Kolodkin A.L., Shipley M.T., Ronnett G.V. Expression of semaphorins in developing and regenerating olfactory epithelium. J. Comp. Neurol. 2000, 423:565-578.
Winkler A.M., Kochunov P., Blangero J., Almasy L., Zilles K., Fox P.T., Duggirala R., Glahn D.C. Cortical thickness or grey matter volume? The importance of selecting the phenotype for imaging genetics studies. NeuroImage 2010, 23:1133-1144.
Winterer G., Konrad A., Vucurevic G., Musso F., Stoeter P., Dahmen N. Association of 5' end neuregulin-1 (NRG1) gene variation with subcortical medial frontal microstructure in humans. NeuroImage 2008, 40:712-718.