Abstract
As understanding of the genetics of bipolar disorder increases, controversy endures regarding whether the origins of this illness include early maldevelopment. Clarification would be facilitated by a ‘hard’ biological index of fetal developmental abnormality, among which craniofacial dysmorphology bears the closest embryological relationship to brain dysmorphogenesis. Therefore, 3D laser surface imaging was used to capture the facial surface of 21 patients with bipolar disorder and 45 control subjects; 21 patients with schizophrenia were also studied. Surface images were subjected to geometric morphometric analysis in non-affine space for more incisive resolution of subtle, localised dysmorphologies that might distinguish patients from controls. Complex and more biologically informative, non-linear changes distinguished bipolar patients from control subjects. On a background of minor dysmorphology of the upper face, maxilla, midface and periorbital regions, bipolar disorder was characterised primarily by the following dysmorphologies: (a) retrusion and shortening of the premaxilla, nose, philtrum, lips and mouth (the frontonasal prominences), with (b) some protrusion and widening of the mandible-chin. The topography of facial dysmorphology in bipolar disorder indicates disruption to early development in the frontonasal process and, on embryological grounds, cerebral dysmorphogenesis in the forebrain, most likely between the 10th and 15th week of fetal life.
Highlights
Increased understanding of the genetics of bipolar disorder is revealing shared genetic risk for other illnesses that include the neurodevelopmental condition of attention deficit/hyperactivity disorder as well as schizophrenia (Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2018; Brainstorm Consortium, 2018)
Variance and cumulative variance explained by each principal component (PC), with probability values adjusted for age and sex by a linear regression model for each PC in distinguishing bipolar and schizophrenia patients from controls; p values should be compared to the Bonferroni adjusted significance level 0.05/ 10 = 0.005
Following adjustment for age and sex, PC1 distinguished bipolar disorder cases from controls (p = 0.003, Table 1; Bonferroni significance level 0.05/10 = 0.005), with no diagnosis × sex interaction; no PC was informative in distinguishing schizophrenia cases from controls at the indicated level of significance
Summary
Increased understanding of the genetics of bipolar disorder is revealing shared genetic risk for other illnesses that include the neurodevelopmental condition of attention deficit/hyperactivity disorder as well as schizophrenia (Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2018; Brainstorm Consortium, 2018). While the neurodevelopmental model continues to hold ‘centre stage’ in relation to schizophrenia (Waddington et al, 2012; Weinberger, 2017), controversy endures regarding the extent to which bipolar disorder might have developmental origins (Sanches et al, 2008; Demjaha et al, 2012; Parellada et al, 2017) Clarification of this controversy would be facilitated by a ‘hard’ biological index of developmental abnormality. In the studies outlined above, craniofacial dysmorphology was quantified in terms of overall differences in craniofacial shape between cases and controls These analyses, involving generalised Procrustes registration in order to describe the variation of individual shapes around a mean (Goodall, 1991), have focussed conventionally on all types of deformations at given locations on surfaces, including those that operate uniformly across the surface at large scale. As recently described (Katina, 2012), it is possible to resolve more complex changes in non-affine space in which deformation at given locations is not assumed to be uniform, to reflect the practical reality that each location often has a distinct structural environment (Wen et al, 2012; Hufnagel, 2015)
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