Discovery and Replication of Dopamine-related Gene Effects on Caudate Volume in Young and Elderly Populations (N=1198) Using Genome-wide Search

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2011 Apr 20

PMID 21502949

Citations 38

Authors

J L Stein

D P Hibar

S K Madsen

M Khamis

K L McMahon

G I de Zubicaray

N K Hansell

G W Montgomery

N G Martin

M J Wright

A J Saykin

C R Jack Jr

M W Weiner

A W Toga

P M Thompson

Affiliations

Soon will be listed here.

Abstract

The caudate is a subcortical brain structure implicated in many common neurological and psychiatric disorders. To identify specific genes associated with variations in caudate volume, structural magnetic resonance imaging and genome-wide genotypes were acquired from two large cohorts, the Alzheimer's Disease NeuroImaging Initiative (ADNI; N=734) and the Brisbane Adolescent/Young Adult Longitudinal Twin Study (BLTS; N=464). In a preliminary analysis of heritability, around 90% of the variation in caudate volume was due to genetic factors. We then conducted genome-wide association to find common variants that contribute to this relatively high heritability. Replicated genetic association was found for the right caudate volume at single-nucleotide polymorphism rs163030 in the ADNI discovery sample (P=2.36 × 10⁻⁶) and in the BLTS replication sample (P=0.012). This genetic variation accounted for 2.79 and 1.61% of the trait variance, respectively. The peak of association was found in and around two genes, WDR41 and PDE8B, involved in dopamine signaling and development. In addition, a previously identified mutation in PDE8B causes a rare autosomal-dominant type of striatal degeneration. Searching across both samples offers a rigorous way to screen for genes consistently influencing brain structure at different stages of life. Variants identified here may be relevant to common disorders affecting the caudate.

Citing Articles

Is There a Natural, Non-addictive, and Non-anti-reward, Safe, Gene-based Solution to Treat Reward Deficiency Syndrome? KB220 Variants vs GLP-1 Analogs.

Modestino E, Bowirrat A, Baron D, Thanos P, Hanna C, Bagchi D J Addict Psychiatry. 2024; 8(1):34-49.

PMID: 39618491 PMC: 11606528.

Subjective well-being can be predicted by caudate volume and promotion focus.

Matsunaga M, Ohtsubo Y, Ishii K, Tsuboi H, Suzuki K, Takagishi H Brain Struct Funct. 2024; 229(9):2315-2326.

PMID: 39066916 DOI: 10.1007/s00429-024-02830-3.

Self-supervised multimodal learning for group inferences from MRI data: Discovering disorder-relevant brain regions and multimodal links.

Fedorov A, Geenjaar E, Wu L, Sylvain T, DeRamus T, Luck M Neuroimage. 2023; 285:120485.

PMID: 38110045 PMC: 10872501. DOI: 10.1016/j.neuroimage.2023.120485.

Genome-wide association and replication studies for handedness in a Korean community-based cohort.

Song Y, Lee D, Choi J, Lee J, Hong K Brain Behav. 2023; 13(9):e3121.

PMID: 37337823 PMC: 10498080. DOI: 10.1002/brb3.3121.

Striatal fibrinogen extravasation and vascular degeneration correlate with motor dysfunction in an aging mouse model of Alzheimer's disease.

Berk-Rauch H, Choudhury A, Richards A, Singh P, Chen Z, Norris E Front Aging Neurosci. 2023; 15:1064178.

PMID: 36967821 PMC: 10034037. DOI: 10.3389/fnagi.2023.1064178.

References

Ryu S, Mahler J, Acampora D, Holzschuh J, Erhardt S, Omodei D . Orthopedia homeodomain protein is essential for diencephalic dopaminergic neuron development. Curr Biol. 2007; 17(10):873-80. DOI: 10.1016/j.cub.2007.04.003. View

Larisch R, Meyer W, Klimke A, Kehren F, Vosberg H . Left-right asymmetry of striatal dopamine D2 receptors. Nucl Med Commun. 1998; 19(8):781-7. DOI: 10.1097/00006231-199808000-00009. View

Dick D, Aliev F, Krueger R, Edwards A, Agrawal A, Lynskey M . Genome-wide association study of conduct disorder symptomatology. Mol Psychiatry. 2010; 16(8):800-8. PMC: 3580835. DOI: 10.1038/mp.2010.73. View

Madsen S, Ho A, Hua X, Saharan P, Toga A, Jack Jr C . 3D maps localize caudate nucleus atrophy in 400 Alzheimer's disease, mild cognitive impairment, and healthy elderly subjects. Neurobiol Aging. 2010; 31(8):1312-25. PMC: 2903198. DOI: 10.1016/j.neurobiolaging.2010.05.002. View

Kathiresan S, Willer C, Peloso G, Demissie S, Musunuru K, Schadt E . Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2008; 41(1):56-65. PMC: 2881676. DOI: 10.1038/ng.291. View

Manolio T, Collins F, Cox N, Goldstein D, Hindorff L, Hunter D . Finding the missing heritability of complex diseases. Nature. 2009; 461(7265):747-53. PMC: 2831613. DOI: 10.1038/nature08494. View

Peterson B, Riddle M, Cohen D, Katz L, Smith J, Leckman J . Human basal ganglia volume asymmetries on magnetic resonance images. Magn Reson Imaging. 1993; 11(4):493-8. DOI: 10.1016/0730-725x(93)90468-s. View

Perez-Torres S, Cortes R, Tolnay M, Probst A, Palacios J, Mengod G . Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer's disease brains examined by in situ hybridization. Exp Neurol. 2003; 182(2):322-34. DOI: 10.1016/s0014-4886(03)00042-6. View

Harris G, Pearlson G, Peyser C, Aylward E, Roberts J, Barta P . Putamen volume reduction on magnetic resonance imaging exceeds caudate changes in mild Huntington's disease. Ann Neurol. 1992; 31(1):69-75. DOI: 10.1002/ana.410310113. View

10.

Morra J, Tu Z, Apostolova L, Green A, Avedissian C, Madsen S . Validation of a fully automated 3D hippocampal segmentation method using subjects with Alzheimer's disease mild cognitive impairment, and elderly controls. Neuroimage. 2008; 43(1):59-68. PMC: 2624575. DOI: 10.1016/j.neuroimage.2008.07.003. View

11.

Goldman A, Pezawas L, Mattay V, Fischl B, Verchinski B, Zoltick B . Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study. Biol Psychiatry. 2007; 63(5):475-83. DOI: 10.1016/j.biopsych.2007.06.006. View

12.

Kuhlenbaumer G, Ludemann P, Schirmacher A, De Vriendt E, Hunermund G, Young P . Autosomal dominant striatal degeneration (ADSD): clinical description and mapping to 5q13-5q14. Neurology. 2004; 62(12):2203-8. DOI: 10.1212/01.wnl.0000130485.89814.10. View

13.

Shaw P, Lerch J, Pruessner J, Taylor K, Rose A, Greenstein D . Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007; 6(6):494-500. DOI: 10.1016/S1474-4422(07)70106-0. View

14.

Hickie I, Naismith S, Ward P, Scott E, Mitchell P, Schofield P . Serotonin transporter gene status predicts caudate nucleus but not amygdala or hippocampal volumes in older persons with major depression. J Affect Disord. 2006; 98(1-2):137-42. DOI: 10.1016/j.jad.2006.07.010. View

15.

Appenzeller S, Schirmacher A, Halfter H, Baumer S, Pendziwiat M, Timmerman V . Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene. Am J Hum Genet. 2010; 86(1):83-7. PMC: 2801755. DOI: 10.1016/j.ajhg.2009.12.003. View

16.

Durston S, Fossella J, Casey B, Hulshoff Pol H, Galvan A, Schnack H . Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls. Mol Psychiatry. 2005; 10(7):678-85. DOI: 10.1038/sj.mp.4001649. View

17.

Peper J, Brouwer R, Boomsma D, Kahn R, Hulshoff Pol H . Genetic influences on human brain structure: a review of brain imaging studies in twins. Hum Brain Mapp. 2007; 28(6):464-73. PMC: 6871295. DOI: 10.1002/hbm.20398. View

18.

Looi J, Lindberg O, Liberg B, Tatham V, Kumar R, Maller J . Volumetrics of the caudate nucleus: reliability and validity of a new manual tracing protocol. Psychiatry Res. 2008; 163(3):279-88. DOI: 10.1016/j.pscychresns.2007.07.005. View

19.

Nicola S, Surmeier J, Malenka R . Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens. Annu Rev Neurosci. 2000; 23:185-215. DOI: 10.1146/annurev.neuro.23.1.185. View

20.

Ling K, Hewitt C, Beissbarth T, Hyde L, Banerjee K, Cheah P . Molecular networks involved in mouse cerebral corticogenesis and spatio-temporal regulation of Sox4 and Sox11 novel antisense transcripts revealed by transcriptome profiling. Genome Biol. 2009; 10(10):R104. PMC: 2784319. DOI: 10.1186/gb-2009-10-10-r104. View