15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia

Abstract

Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.

Figure 1

Association of the 15q11.2(BP1–BP2) deletion group and subgroups of NoCNV with cognitive traits, GAF, ARHQ, AMHQ and functional MRI test scores. (a) Average standardized scores for 15q11.2(BP1–BP2) deletion, DLX&DC and NoCNV without (w/o) learning difficulties. (b) Average standardized scores for DLXonly, DConly and NoCNV w/o learning difficulties. (c) Mean accuracy for fMRI phonological lexical decision tasks (words) and multiplication verification tasks (mult) for 15q11.2(BP1–BP2) deletion, DLXonly, DConly, DLX&DC and NoCNV. The tests are verbal IQ (V-IQ); performance IQ (P-IQ); logical memory I and II (LM I and II); letter fluency (LF); category fluency (CF); Stroop (the difference between the time it takes to name the color of the ink of a word that is actually the name of another color and to name the color of colorpads); trail making test (TMT), TMT trail B–TMT trail A; perseverative errors in the Wisconsin card sorting test (Pers. Err); spatial working memory (SWM); rapid visual information processing (RVIP); TMT trail A (TMT-A); Str-bl (Stroop: time it takes to read the names of colors written in black ink); global assessment of function (GAF); adult reading history questionnaire (ARHQ); adult mathematical history questionnaire (AMHQ). Word experiment: orthographic familiar forms of Icelandic nouns (W); phonologically correct but orthographically unfamiliar forms of the same word (PH); phonologically and orthographically unfamiliar forms (PW); false fonts (FF). Multiplication experiment: correct equation (C); incorrect equation (NC); false equation (F). See previous study for more information about tests in a and b, and the functional MRI section below for more information about tests in c. Error bars represent standard error. Impairment is in s.d. units. The sample size given in the figure legend for a and b refer to the number of subjects with available scores. Some individual scores are missing. The sample size for each test is given in Supplementary Table 2. CNV, copy number variation; DC, dyscalculic; DConly, dyscalculic but not dyslexic; DLX, dyslexic; DLX&DC, dyslexic and dyscalculic; DLXonly, dyslexic but not dyscalculic; IQ, intelligence quotient; MRI, magnetic resonance imaging.

Figure 2

The effect of the CNV carrier status (deletion, PopCtrl, duplication) on gray matter volume difference. The T-scores for the CNV carrier status are displayed where findings are highlighted in red or blue if P<0.001 with red indicating less gray matter volume for the 15q11.2(BP1–BP2) deletion carriers, and blue indicating greater volume. The first three figures are sagittal slices while the last figure shows a coronal slice where the location of the sagittal slices are denoted by vertical lines. CNV, copy number variation.

Figure 3

The effect of the CNV carrier status (deletion, PopCtrl, duplication) on white matter volume change. The T-scores for the CNV carrier status are displayed where findings are highlighted in red or blue if P<0.001 with red indicating less white matter volume for the 15q11.2(BP1–BP2) deletion carriers, and blue indicating greater volume. The first five images are axial slices (inferior to superior). The rightmost image shows the locations of the axial slices on a sagittal view. CNV, copy number variation.

Figure 4

Carrier status-dependent functional difference. (a) The word experiment. A sagittal slice (left), x=−28, showing the location, MNI=(−28, −36, −14) of significant carrier status effect on the contrast PW vs W. (b) The multiplication experiment. A sagittal slice (left), x=−50, showing the location, MNI=(−50, −66, 24), of significant carrier status effect on the contrast C vs F. The right images on both a and b show the location of the sagittal slice on a coronal view. C, correct equation; F, false equation; MNI, Montreal Neurological Institute; PW, phonologically and orthographically unfamiliar forms; W, orthographic familiar forms of Icelandic nouns.