Neuroimaging investigations of structural and functional brain abnormalities in subjects at genetic risk for bipolar disorder (BD) offer several advantages. They are not confounded by illness duration or exposure to previous treatments and may ultimately inform evaluation of risk for subsequent development of BD and subsequent therapeutic intervention [
4]. Although a number of imaging studies in subjects at high risk (HR) for BD are available, the results are conflicting and no reliable imaging markers of genetic liability to BD is clinically available yet [
5‐
8].
In a recent systematic meta-analysis of neuroimaging studies of 996 HR subjects for BD and 1258 controls, we confirmed inconclusive structural findings but increased neurofunctional response during cognitive tasks in the prefrontal and temporo-insular regions [
9]. On the basis of the study by Benedetti et al. [
3] it is possible to speculate that temporo-limbic white matter (WM) alterations may alter the neurofunctional connectivity and ultimately the regional response during cognitive tasks. Specifically, region-of-interest magnetic resonance imaging (MRI) studies of twins found decreased left hemispheric WM volume in either BD patients or co-twins (HR) compared with control twin subjects [
10]. This indicated that genes involved in the etiology of BD may contribute to the WM decreases found in BD patients and in their co-twins (HR) (trait markers) [
11]. However, other MRI studies reported contrasting findings with no significant WM alterations in the HR as compared to controls [
12,
13] or to BD [
14]. Others suggested more circumscribed and limited WM alterations in the major tracts of the brain [
15] in line with the findings of Benedetti et al. [
3]. DTI studies in the HR group showed reduced FA in the superior longitudinal fasciculus as compared to controls [
6] and FA in HR intermediate to controls and BD patients [
16]. Significant reductions in the number, density, and size of glial cells could be reflected in reduced WM tissue and signal hyperintensities, which are often reported in HR subjects [
6].
The genetics of bipolar disorder is complex and relatives are most likely to carry some risk allels [
11], unaffected relatives of BD patients are likely to share some susceptibility genes with affected patients. We therefore suggest that WM alterations may represent endophenotypes and neurobiological markers intermediate between the underlying susceptibility genes and the clinical expression of BD. A recently published study of monozygotic and dizygotic twin pairs revealed segregating genetic liabilities specifically associated with thicker right parietal cortex in schizophrenia and larger intracranial volume for BD [
7]. However, disruptions in WM integrity have been implicated as endophenotype in schizophrenia and evidence includes neuroimaging studies of first-episode and chronic patients that report WM volume reductions and structural abnormalities, as well as myelin-related gene abnormalities [
17]. Overlapping WM alterations between these two HR groups raises the possibility that schizophrenia and bipolar disorders share common endophenotypes [
18‐
21].