Publications

Abstract

Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3′UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease

Abstract

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.

Abstract

Left-right laterality is an important aspect of human –and in fact all vertebrate– brain organization for which the genetic basis is poorly understood. Using RNA sequencing data we contrasted gene expression in left- and right-sided samples from several structures of the anterior central nervous systems of post mortem human embryos and foetuses. While few individual genes stood out as significantly lateralized, most structures showed evidence of laterality of their overall transcriptomic profiles. These left-right differences showed overlap with age-dependent changes in expression, indicating lateralized maturation rates, but not consistently in left-right orientation over all structures. Brain asymmetry may therefore originate in multiple locations, or if there is a single origin, it is earlier than 5 weeks post conception, with structure-specific lateralized processes already underway by this age. This pattern is broadly consistent with the weak correlations reported between various aspects of adult brain laterality, such as language dominance and handedness.

Abstract

Left-right asymmetry is subtle but pervasive in the human central nervous system. This asymmetry is initiated early during development, but its mechanisms are poorly known. Forebrains and midbrains were dissected from six human embryos at Carnegie stages 15 or 16, one of which was female. The structures were divided into left and right sides, and RNA was isolated. RNA was sequenced with 100 base-pair paired ends using Illumina Hiseq 4000. After quality control, five paired brain sides were available for midbrain and forebrain. A paired analysis between left- and right sides of a given brain structure across the embryos identified left-right differences. The dataset, consisting of Fastq files and a read count table, can be further used to study early development of the human brain

Abstract

Twin studies indicate that additive genetic effects explain most of the variance in nicotine dependence (ND), a construct emphasizing habitual heavy smoking despite adverse consequences, tolerance and withdrawal. To detect ND alleles, we assessed cigarettes per day (CPD) regularly smoked, in two European populations via whole genome association techniques. In these approximately 7500 persons, a common haplotype in the CHRNA3-CHRNA5 nicotinic receptor subunit gene cluster was associated with CPD (nominal P=6.9 x 10(-5)). In a third set of European populations (n= approximately 7500) which had been genotyped for approximately 6000 SNPs in approximately 2000 genes, an allele in the same haplotype was associated with CPD (nominal P=2.6 x 10(-6)). These results (in three independent populations of European origin, totaling approximately 15 000 individuals) suggest that a common haplotype in the CHRNA5/CHRNA3 gene cluster on chromosome 15 contains alleles, which predispose to ND.

Abstract

It was recently suggested that the Kibra polymorphism rs17070145 has a strong effect on multiple episodic memory tasks in humans. We attempted to replicate this using two cohorts of European genetic origin (n = 319 and n = 365). We found no association with either the original SNP or a set of tagging SNPs in the Kibra gene with multiple verbal memory tasks, including one that was an exact replication (Auditory Verbal Learning Task, AVLT). These results suggest that Kibra does not have a strong and general effect on human memory.

Abstract

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Abstract

Several quantitative trait loci (QTLs) that influence developmental dyslexia (reading disability [RD]) have been mapped to chromosome regions by linkage analysis. The most consistently replicated area of linkage is on chromosome 6p23-21.3. We used association analysis in 223 siblings from the United Kingdom to identify an underlying QTL on 6p22.2. Our association study implicates a 77-kb region spanning the gene TTRAP and the first four exons of the neighboring uncharacterized gene KIAA0319. The region of association is also directly upstream of a third gene, THEM2. We found evidence of these associations in a second sample of siblings from the United Kingdom, as well as in an independent sample of twin-based sibships from Colorado. One main RD risk haplotype that has a frequency of ∼12% was found in both the U.K. and U.S. samples. The haplotype is not distinguished by any protein-coding polymorphisms, and, therefore, the functional variation may relate to gene expression. The QTL influences a broad range of reading-related cognitive abilities but has no significant impact on general cognitive performance in these samples. In addition, the QTL effect may be largely limited to the severe range of reading disability.

Abstract

Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are common highly heritable disorders of childhood, which frequently co-occur. Data from twin and family studies suggest that this overlap is, in part, due to shared genetic underpinnings. Here, we report the first genome-wide linkage analysis of measures of reading ability in children with ADHD, using a sample of 233 affected sibling pairs who previously participated in a genome-wide scan for susceptibility loci in ADHD. Quantitative trait locus (QTL) analysis of a composite reading factor defined from three highly correlated reading measures identified suggestive linkage (multipoint maximum lod score, MLS>2.2) in four chromosomal regions. Two regions (16p, 17q) overlap those implicated by our previous genome-wide scan for ADHD in the same sample: one region (2p) provides replication for an RD susceptibility locus, and one region (10q) falls approximately 35 cM from a modestly highlighted region in an independent genome-wide scan of siblings with ADHD. Investigation of an individual reading measure of Reading Recognition supported linkage to putative RD susceptibility regions on chromosome 8p (MLS=2.4) and 15q (MLS=1.38). Thus, the data support the existence of genetic factors that have pleiotropic effects on ADHD and reading ability--as suggested by shared linkages on 16p, 17q and possibly 10q--but also those that appear to be unique to reading--as indicated by linkages on 2p, 8p and 15q that coincide with those previously found in studies of RD. Our study also suggests that reading measures may represent useful phenotypes in ADHD research. The eventual identification of genes underlying these unique and shared linkages may increase our understanding of ADHD, RD and the relationship between the two.

Abstract

We completed fine mapping of nine positional candidate regions for attention-deficit/hyperactivity disorder (ADHD) in an extended population sample of 308 affected sibling pairs (ASPs), constituting the largest linkage sample of families with ADHD published to date. The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in our sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=.024) and 17p11 (MLS 3.63; empiric P=.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions—5p13, 6q12, 16p13, and 17p11—are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size.