Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology

Abstract

The NRXN1 locus is a hotspot for non-recurrent copy number variants and exon-disrupting NRXN1 deletions have been associated with increased risk of neurodevelopmental disorders in case-control studies. However, corresponding population-based estimates of prevalence and disease-associated risk are currently lacking. Also, most studies have not differentiated between deletions affecting exons of different NRXN1 splice variants nor considered intronic deletions. We used the iPSYCH2015 case-cohort sample to obtain unbiased estimates of the prevalence of NRXN1 deletions and their associated risk of autism, schizophrenia, depression, and ADHD. Most exon-disrupting deletions affected exons specific to the alpha isoform, and almost half of the non-exonic deletions represented a previously reported segregating founder deletion. Carriage of exon-disrupting NRXN1 deletions was associated with a threefold and twofold increased risk of autism and ADHD, respectively, whereas no significantly increased risk of depression or schizophrenia was observed. Our results highlight the importance of using population-based samples in genetic association studies.

Fig. 1. NRXN1 deletions similarity matrices, and NRXN1 correlation matrix. Note that the NRXN1 gene is encoded on the reverse strand, meaning the alpha promoter region (5′ of the gene) is shown on the right in this figure (see panel c for a breakdown of the gene structure).

a Similarity heatmap for all deletions in the neurexin locus. Similarity is measured as IOU (intersection over the union), as described in the methods. Each row represents a deletion. Deletions are ordered on the x-axis based on the genomic position of the respective centre. Note that the scale is not linear as CNVs are not distributed equally across the locus. b Positional similarity for intronic deletions. This makes more evident the large group of very homogeneous deletions (marked with the orange bar on the x-axis). This group is referenced as segregating in the main text. c Distribution of the centre position for all exonic deletions in the NRXN1 gene locus. A schematic of the main gene isoform is aligned below the x-axis. The green and red bars mark the two exonic groups described in (d). d Exon correlation matrix. Exons are ordered based on genomic location. Note that the scale is not linear as exons are not distributed equally across the locus (see c). The red bar marks the exons in the “alpha” group and the green in the “beta” group. e A different view on the NRXN1 gene, the top blue graph shows all exons used in the study, while the bottom shows the top isoform.

Fig. 2. Forest plots showing the ORs resulting from three logistic regression analyses on four neurodevelopmental disorders.

a First model, ORs for exonic and non-exonic deletions in the NRXN1 locus. b, c Second model, exonic deletion is divided into three subgroups based on the exons they overlap (alpha promoter region, beta promoter region, at least one of both) and non-exonic are divided into two subgroups (those belonging to the segregating deletion and all the rest). Note that the scale of (b) differs from the rest. d Third model, ORs for being a carrier of the segregating deletion or of the haplotype associated with the deletion but without such deletion.