The population level bias towards right-handedness in humans implies left-hemisphere dominance for fine motor control. Left-handedness and reduced cerebral asymmetry have been linked to neurodevelopmental disorders such as dyslexia. Understanding the biology of these traits at a genetic level is crucial for understanding the relationship between handedness and neurodevelopmental disorders. Here I present genome-wide association study (GWAS) meta-analyses for both relative hand skill (handedness, n = 728) and reading-related traits (n = 548) in individuals with dyslexia. I uncovered a genome-wide significant association in an intron of PCSK6 associated with relative hand skill. PCSK6 is a protease that cleaves NODAL proprotein into an active form, and NODAL determines the development of left/right (LR) asymmetry in bilaterians. I performed pathway analyses of the GWAS data that revealed handedness is determined in part by the mechanisms that establish left/right (LR) asymmetry early in development, such as NODAL signalling and ciliogenesis. This finding replicated in a general population cohort unaffected with neurodevelopmental disorders (n = 2,666). A key stage in LR asymmetry development is the rotation of cilia that creates a leftward flow of NODAL. Candidate genes for dyslexia are involved in both neuronal migration and ciliogenesis. Ciliopathies can cause not only LR body asymmetry phenotypes, but also cerebral midline phenotypes such as an absent corpus callosum. Furthermore, I identified a genome-wide significant association with non-word reading located in an intron of MAP1B, a gene involved in neuronal migration that causes an absent corpus callosum when disrupted in mice. However, this finding did not replicate in two independent cohorts with dyslexia (n = 156 & 199), or in the general population cohort (n = 2,359). Though these cohorts had inadequate reading measures and poorly matched ascertainment for dyslexia. I also performed copy number variation (CNV) pathway and burden analyses of 920 individuals with dyslexia and 1,366 unselected controls, but did not find that rare CNVs play a major role in the etiology of dyslexia. Based on these results I propose that common variants in genes responsible for ciliogenesis and corpus callosum development influence traits such as handedness and reading ability.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:596022 |
| Date | January 2014 |
| Creators | Brandler, William M. |
| Contributors | Monaco, Anthony P.; Webber, Caleb; Morris, Andrew P. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:e3b42dba-7077-4ab8-8eb7-14cd198b5a87 |
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