June 1, 2021  |  

Structural variant in the RNA Binding Motif Protein, X-Linked 2 (RBMX2) gene found to be linked to bipolar disorder

Bipolar disorder (BD) is a phenotypically and genetically complex neurological disorder that affects 1% of the worldwide population. There is compelling evidence from family, twin and adoption studies supporting the involvement of a genetic predisposition with estimated heritability up to ~ 80%. The risk in first-degree relatives is ten times higher than in the general population. Linkage and association studies have implicated multiple putative chromosomal loci for BD susceptibility, however no disease genes have yet to be identified. Here, we have fully characterized a ~12 Mb significantly linked (lod score=3.54) genomic region on chromosome Xq24-q27 in an extended family from a genetic isolate that was using long-read single molecule, real-time (SMRT) sequencing. The family segregates BD in at least 4 generations with 16 individuals out of 61 affected. Thus, this family portrays a highly elevated reoccurrence risk compared to the general population. It is expected that the genetic complexity would be reduced in isolated populations, even in genetically complex disorders such as BD, as in the case of this extended family. We selected 16 key individuals from the X-chromosomally linked family to be sequenced. These selected individuals either carried the disease haplotype, were non-carriers of the disease haplotype, or served as married-in controls. We designed a Nimblegen capture array enriching for 5-9 kb fragments spanning the entire 12 Mb region that were then sequenced using long-read SMRT sequencing to screen for causative structural variants (SVs) explaining the increased risk for BD in this extended family. Altogether, 192 SVs were detected in the critically linked region however most of these represented common variants that could be seen across many of the family members regardless of the disease status. One SV stood out that showed perfect segregation among all affected individuals that were carriers of the disease haplotype. This was a 330bp Alu deletion in intron 4 of the RNA Binding Motif Protein, X-Linked 2 (RBMX2) gene that has previously been shown to play a central role in brain development and function. Moreover, Alu elements in general have also previously been associated with at least 37 neurological and neurodegenerative disorders. In order to validate the finding and the functionality of the identified SV further studies like isoform characterization are warranted.

September 22, 2019  |  

Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder.

Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis p-values: 6.8E-05 for bipolar disorder and 8.2E-04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E-05 for schizophrenia and 9.8E-04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3´s association with bipolar disorder.

July 19, 2019  |  

Characterization of a human-specific tandem repeat associated with bipolar disorder and schizophrenia.

Bipolar disorder (BD) and schizophrenia (SCZ) are highly heritable diseases that affect more than 3% of individuals worldwide. Genome-wide association studies have strongly and repeatedly linked risk for both of these neuropsychiatric diseases to a 100 kb interval in the third intron of the human calcium channel gene CACNA1C. However, the causative mutation is not yet known. We have identified a human-specific tandem repeat in this region that is composed of 30 bp units, often repeated hundreds of times. This large tandem repeat is unstable using standard polymerase chain reaction and bacterial cloning techniques, which may have resulted in its incorrect size in the human reference genome. The large 30-mer repeat region is polymorphic in both size and sequence in human populations. Particular sequence variants of the 30-mer are associated with risk status at several flanking single-nucleotide polymorphisms in the third intron of CACNA1C that have previously been linked to BD and SCZ. The tandem repeat arrays function as enhancers that increase reporter gene expression in a human neural progenitor cell line. Different human arrays vary in the magnitude of enhancer activity, and the 30-mer arrays associated with increased psychiatric disease risk status have decreased enhancer activity. Changes in the structure and sequence of these arrays likely contribute to changes in CACNA1C function during human evolution and may modulate neuropsychiatric disease risk in modern human populations. Copyright © 2018. Published by Elsevier Inc.

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