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Astrid C. van der Schot, MSc; Ronald Vonk, MD; Rachel G. H. Brans, MSc; Neeltje E. M. van Haren, PhD; P. Cédric M.P. Koolschijn, MSc; Valerie Nuboer, MSc; Hugo G. Schnack, PhD; G. Caroline M. van Baal, PhD; Dorret I. Boomsma, PhD; Willem A. Nolen, MD, PhD; Hilleke E. Hulshoff Pol, PhD; René S. Kahn, MD, PhD

Arch Gen Psychiatry. 2009;66(2):142-151.

Context  Structural neuroimaging studies suggest the presence of subtle abnormalities in the brains of patients with bipolar disorder. The influence of genetic and/or environmental factors on these brain abnormalities is unknown.

Objective  To investigate the contribution of genetic and environmental factors on brain volume in bipolar disorder.

Design  Magnetic resonance imaging (1.5 T) brain scans of monozygotic (MZ) or dizygotic (DZ) twins concordant and discordant for bipolar disorder were compared with healthy twin pairs.

Setting  Subjects were recruited from the population, the Netherlands Twin Register, and the twin pair cohort at the University Medical Center Utrecht, Utrecht, The Netherlands.

Participants  A total of 234 subjects including 50 affected twin pairs (9 MZ concordant; 15 MZ discordant; 4 DZ concordant; 22 DZ discordant) and 67 healthy twin pairs (39 MZ and 28 DZ) were included.

Main Outcome Measures  Volumes of the intracranium, cerebrum, cerebellum, lateral and third ventricle, and gray and white matter from the cerebrum and frontal, parietal, temporal, and occipital lobes, both with and without correction for lithium use. To estimate the influence of additive genetic, common, and unique environmental factors, structural equation modeling was applied.

Results  Bipolar disorder was associated with a decrease in total cortical volume. Decreases in white matter were related to the genetic risk of developing bipolar disorder (bivariate heritability, 77%; 95% confidence interval, 38% to 100%). Significant environmental correlations were found for cortical gray matter. These relationships all became more pronounced when data were corrected for lithium use.

Conclusions  Focusing on genes controlling white matter integrity may be a fruitful strategy in the quest to discover genes implicated in bipolar disorder. Elucidating the mechanism by which lithium attenuates brain matter loss may lead to the development of neuroprotective drugs.

Author Affiliations: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht (Mss van der Schot, Brans, and Nuboer, Mr Koolschijn, and Drs van Haren, Schnack, van Baal, Hulshoff Pol, and Kahn); the Reinier van Arkel Group, ’s-Hertogenbosch (Dr Vonk); Department of Biological Psychology, Free University Amsterdam, Amsterdam (Dr Boomsma); and Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (Dr Nolen).

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