Gene-Based Analysis of Regionally Enriched Cortical Genes in GWAS Data Sets of Cognitive Traits and Psychiatric Disorders

Background: Despite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain. It has been suggested that genes preferentially, or specifically, expressed in one region or organ reflect functional specialisation. Employing a gene-based approach to the analysis, we used the regionally enriched cortical genes to mine a genome-wide association study (GWAS) of the Norwegian Cognitive NeuroGenetics (NCNG) sample of healthy adults for association to nine psychometric tests measures. In addition, we explored GWAS data sets for the serious psychiatric disorders schizophrenia (SCZ) (n = 3 samples) and bipolar affective disorder (BP) (n = 3 samples), to which cognitive impairment is linked. Principal Findings: At the single gene level, the temporal cortex enriched gene RAR-related orphan receptor B (RORB) showed the strongest overall association, namely to a test of verbal intelligence (Vocabulary, P = 7.7E-04). We also applied gene set enrichment analysis (GSEA) to test the candidate genes, as gene sets, for enrichment of association signal in the NCNG GWAS and in GWASs of BP and of SCZ. We found that genes differentially expressed in the temporal cortex showed a significant enrichment of association signal in a test measure of non-verbal intelligence (Reasoning) in the NCNG sample. Conclusion: Our gene-based approach suggests that RORB could be involved in verbal intelligence differences, while the genes enriched in the temporal cortex might be important to intellectual functions as measured by a test of reasoning in the healthy population. These findings warrant further replication in independent samples on cognitive traits

Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldGlaucoma is a leading cause of irreversible blindness. A genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q24.1 region associated with glaucoma. Further investigation revealed that the association is confined to exfoliation glaucoma (XFG). Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS). About 25% of the general population is homozygous for the highest-risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low-risk haplotypes. The population-attributable risk is more than 99%. The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG

Sequence variants affecting voice pitch in humans

The genetic basis of the human vocal system is largely unknown, as are the sequence variants that give rise to individual differences in voice and speech. Here, we couple data on diversity in the sequence of the genome with voice and vowel acoustics in speech recordings from 12,901 Icelanders. We show how voice pitch and vowel acoustics vary across the life span and correlate with anthropometric, physiological, and cognitive traits. We found that voice pitch and vowel acoustics have a heritable component and discovered correlated common variants in ABCC9 that associate with voice pitch. The ABCC9 variants also associate with adrenal gene expression and cardiovascular traits. By showing that voice and vowel acoustics are influenced by genetics, we have taken important steps toward understanding the genetics and evolution of the human vocal system.Published versiondeCODE genetics/Amgen Inc. funded the study

Variants conferring risk of atrial fibrillation on chromosome 4q25.

To access publisher full text version of this article. Please click on the hyperlink in Additional Link fieldAtrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart

Long-read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits.

To access publisher's full text version of this article click on the hyperlink belowLong-read sequencing (LRS) promises to improve the characterization of structural variants (SVs). We generated LRS data from 3,622 Icelanders and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions). We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association of a rare deletion in PCSK9 with lower low-density lipoprotein (LDL) cholesterol levels, compared to the population average. We also discovered an association of a multiallelic SV in ACAN with height; we found 11 alleles that differed in the number of a 57-bp-motif repeat and observed a linear relationship between the number of repeats carried and height. These results show that SVs can be accurately characterized at the population scale using LRS data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes

A genetic risk factor for periodic limb movements in sleep

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. METHODS: To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. RESULTS: In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). CONCLUSIONS: We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease

Schematic overview of the method.

<p>SNP markers from GWAS data were assigned to single genes in a process termed “gene binning”, by implementing a novel LD-based tool (LDsnpR, Christoforou <i>et al.</i> under revision). Modified Sidak's <i>P</i>-values were extracted for each gene (“gene bin”) in the GWAS data sets. Single gene-based analysis of the differentially expressed cortical genes was performed by extracting the modified Sidak's <i>P</i>-values for the candidate genes from the NCNG GWAS. Gene set-based analysis of the differentially expressed cortical genes was performed by extraction of the modified Sidak's <i>P</i>-values, followed by GSEA of GWAS data on cognition, psychiatric disorders and non-psychiatric phenotypes. GSEA: Gene set enrichment analysis, GWAS: Genome-wide association study.</p

Functional characterisation of the human homologues to the rat regionally enriched cortical genes.

<p>Search for over- and under-represented biological processes and molecular functions was performed by using Panther <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Thomas1" target="_blank">[35]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Mi1" target="_blank">[36]</a>. The significance of over- and under-represented Panther classification categories in the complete list of candidate genes (i.e. all the cortical regions, column 2), the FMCx enriched genes (column 3), TCx enriched genes (column 4) and OCx enriched genes (column 5), is illustrated by a heat map. The statistical significance of each gene set (negative log <i>P</i>-value) is illustrated by colour intensity (red: over-represented, blue: under-represented, white: as expected). Number of genes in each gene set is listed. The OCx gene <i>HTR5B</i> was not represented in Panther. The percentage of genes within a gene set that map to the given category is indicated on the heat map, e.g. 59% of the 61 enriched genes map to the biological process “cellular process”. The first column states the overall distribution of a term among the 19,911 genes from the default human reference gene list, e.g. 31% of the 61 regional genes were expected to map to ‘“cellular process”, hence this category is significantly over-represented among the regional genes. Exp: expected (based on default human reference gene list), FMCx: frontomedial cortex, TCx: temporal cortex, OCx: occipital cortex, #: number of genes in each gene set, %: percentage of genes.</p

GSEA of differentially expressed cortical genes in psychiatric disorders and non-psychiatric phenotypes.

<p>GSEA was used to analyse the differentially expressed cortical genes, as gene sets, for enrichment of association signal in three different BP GWASs (a German sample, the Norwegian TOP sample and the British WTCCC BP sample <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Cichon1" target="_blank">[20]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Djurovic1" target="_blank">[41]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-WTCCC1" target="_blank">[42]</a>), three SCZ GWASs (the Norwegian TOP sample, the German part of a combined German-Dutch SCZ GWAS and a Danish sample <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Rietschel1" target="_blank">[19]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Athanasiu1" target="_blank">[43]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Ingason1" target="_blank">[44]</a>) and six non-psychiatric phenotypes (from WTCCC; CD: Crohn's disease, CHD: coronary heart disease, HT: hypertension, RA: rheumatoid arthritis, T1D: type 1 diabetes and T2D: type 2 diabetes, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-WTCCC1" target="_blank">[42]</a>). The analysis was based on extraction of modified Sidak's minimum <i>P</i>-values <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Saccone1" target="_blank">[45]</a>, as implemented in LDsnpR. FDR q-value<0.1 was set as cut-off value for significant enrichment.</p>*<p>: One FMCx gene was not represented in the data set.</p>**<p>: Two FMCx genes were not represented in the data set.</p