The corpus callosum is the brain's largest commissural fiber tract and is crucial for interhemispheric integration of neural information. Despite the high relevance of the corpus callosum for several cognitive systems, the molecular determinants of callosal microstructure are largely unknown. Recently, it was shown that genetic variations in the myelin-related proteolipid 1 gene PLP1 and the axon guidance related contactin 1 gene CNTN1 were associated with differences in interhemispheric integration at the behavioral level. Here, we used an innovative new diffusion neuroimaging technique called neurite orientation dispersion and density imaging (NODDI) to quantify axonal morphology in subsections of the corpus callosum and link them to genetic variation in PLP1 and CNTN1. In a cohort of 263 healthy human adults, we found that polymorphisms in both PLP1 and CNTN1 were significantly associated with callosal microstructure. Importantly, we found a double dissociation between gene function and neuroimaging variables. Our results suggest that genetic variation in the myelin-related gene PLP1 impacts white matter microstructure in the corpus callosum, possibly by affecting myelin structure. In contrast, genetic variation in the axon guidance related gene CNTN1 impacts axon density in the corpus callosum. These findings suggest that PLP1 and CNTN1 gene variations modulate specific aspects of callosal microstructure that are in line with their gene function.

Cognitive Neurophysiology Department of Child and Adolescent Psychiatry Faculty of Medicine TU Dresden Dresden Germany Experimental Neurobiology National Institute of Mental Health Topolova 748 25067 Klecany Czech Republic

Department of Human Genetics Ruhr University Bochum Bochum Germany

Department of Human Genetics Ruhr University Bochum Bochum Germany Faculty of Health ZBAF University of Witten Herdecke Witten Germany

Department of Psychology University of Otago P O Box 56 Dunedin New Zealand Institute of Cognitive Neuroscience Biopsychology Department of Psychology Ruhr University Bochum Bochum Germany

Faculty of Health ZBAF University of Witten Herdecke Witten Germany

Institute of Cognitive Neuroscience Biopsychology Department of Psychology Ruhr University Bochum Bochum Germany

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