Identifying novel regulatory effects for clinically relevant genes through the study of the Greek population.

BACKGROUND: Expression quantitative trait loci (eQTL) studies provide insights into regulatory mechanisms underlying disease risk. Expanding studies of gene regulation to underexplored populations and to medically relevant tissues offers potential to reveal yet unknown regulatory variants and to better understand disease mechanisms. Here, we performed eQTL mapping in subcutaneous (S) and visceral (V) adipose tissue from 106 Greek individuals (Greek Metabolic study, GM) and compared our findings to those from the Genotype-Tissue Expression (GTEx) resource. RESULTS: We identified 1,930 and 1,515 eGenes in S and V respectively, over 13% of which are not observed in GTEx adipose tissue, and that do not arise due to different ancestry. We report additional context-specific regulatory effects in genes of clinical interest (e.g. oncogene ST7) and in genes regulating responses to environmental stimuli (e.g. MIR21, SNX33). We suggest that a fraction of the reported differences across populations is due to environmental effects on gene expression, driving context-specific eQTLs, and suggest that environmental effects can determine the penetrance of disease variants thus shaping disease risk. We report that over half of GM eQTLs colocalize with GWAS SNPs and of these colocalizations 41% are not detected in GTEx. We also highlight the clinical relevance of S adipose tissue by revealing that inflammatory processes are upregulated in individuals with obesity, not only in V, but also in S tissue. CONCLUSIONS: By focusing on an understudied population, our results provide further candidate genes for investigation regarding their role in adipose tissue biology and their contribution to disease risk and pathogenesis.

Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome.

While the recurrent 22q11.2 deletion is one of the strongest genetic risk factors for schizophrenia (SCZ), variability of its associated neuropsychiatric endophenotypes reflects its incomplete penetrance for psychosis development. To assess whether this phenotypic variability is linked to common variants associated with SCZ, we studied the association between SCZ polygenic risk score (PRS) and longitudinally acquired phenotypic information of the Swiss 22q11.2DS cohort (n = 97, 50% females, mean age 17.7 yr, mean visit interval 3.8 yr). The SCZ PRS with the best predictive performance was ascertained in the Estonian Biobank (n = 201,146) with LDpred. The infinitesimal SCZ PRS model showed the strongest capacity in discriminating SCZ cases from controls with one SD difference in SCZ PRS corresponding to an odds ratio (OR) of 1.73 (95% CI 1.57-1.90, P = 1.47 × 10-29). In 22q11.2 patients, random-effects ordinal regression modelling using longitudinal data showed SCZ PRS to have the strongest effect on social anhedonia (OR = 2.09, P = 0.0002), and occupational functioning (OR = 1.82, P = 0.0003) within the negative symptoms course, and dysphoric mood (OR = 2.00, P = 0.002) and stress intolerance (OR = 1.76, P = 0.0002) within the general symptoms course. Genetic liability for SCZ was additionally associated with full scale cognitive decline (ß = -0.25, P = 0.02) and with longitudinal volumetric reduction of the right and left hippocampi (ß = -0.28, P = 0.005; ß = -0.23, P = 0.02, respectively). Our results indicate that the polygenic contribution to SCZ acts upon the threshold-lowering first hit (i.e., the deletion). It modifies the endophenotypes of 22q11.2DS and augments the derailment of developmental trajectories of negative and general symptoms, cognition, and hippocampal volume.

Putative cis-regulatory drivers in colorectal cancer.

The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis. To better characterize colorectal cancer (CRC) development we conducted an RNA-sequencing experiment of 103 matched tumour and normal colon mucosa samples from Danish CRC patients, 90 of which were germline-genotyped. By investigating allele-specific expression (ASE) we show that the germline genotypes remain important determinants of allelic gene expression in tumours. Using the changes in ASE in matched pairs of samples we discover 71 genes with excess of somatic cis-regulatory effects in CRC, suggesting a cancer driver role. We correlate genotypes and gene expression to identify expression quantitative trait loci (eQTLs) and find 1,693 and 948 eQTLs in normal samples and tumours, respectively. We estimate that 36% of the tumour eQTLs are exclusive to CRC and show that this specificity is partially driven by increased expression of specific transcription factors and changes in methylation patterns. We show that tumour-specific eQTLs are more enriched for low CRC genome-wide association study (GWAS) P values than shared eQTLs, which suggests that some of the GWAS variants are tumour specific regulatory variants. Importantly, tumour-specific eQTL genes also accumulate more somatic mutations when compared to the shared eQTL genes, raising the possibility that they constitute germline-derived cancer regulatory drivers. Collectively the integration of genome and the transcriptome reveals a substantial number of putative somatic and germline cis-regulatory cancer changes that may have a role in tumorigenesis.

Tissue-specific effects of genetic and epigenetic variation on gene regulation and splicing.

Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. In this study, we use the GenCord cohort of 204 newborn Europeans' lymphoblastoid cell lines, T-cells and fibroblasts derived from umbilical cords. The samples were previously genotyped for 2.5 million SNPs, mRNA-sequenced, and assayed for methylation levels in 482,421 CpG sites. We observe that methylation sites associated to expression levels are enriched in enhancers, gene bodies and CpG island shores. We show that while the correlation between DNA methylation and gene expression can be positive or negative, it is very consistent across cell-types. However, this epigenetic association to gene expression appears more tissue-specific than the genetic effects on gene expression or DNA methylation (observed in both sharing estimations based on P-values and effect size correlations between cell-types). This predominance of genetic effects can also be reflected by the observation that allele specific expression differences between individuals dominate over tissue-specific effects. Additionally, we discover genetic effects on alternative splicing and interestingly, a large amount of DNA methylation correlating to alternative splicing, both in a tissue-specific manner. The locations of the SNPs and methylation sites involved in these associations highlight the participation of promoter proximal and distant regulatory regions on alternative splicing. Overall, our results provide high-resolution analyses showing how genome sequence variation has a broad effect on cellular phenotypes across cell-types, whereas epigenetic factors provide a secondary layer of variation that is more tissue-specific. Furthermore, the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole.

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.

Calidad de sueño en Uruguay al inicio de la pandemia / Sleep quality in Uruguay at the beginning of the pandemic / Qualidade do sono no Uruguai no início da pandemia

El año 2020 será recordado por el comienzo de la pandemia de COVID-19, la que ha generado trágicas consecuencias para la salud personal y social. Además de los fallecimientos, contagios y el temor a estos, se redujo considerablemente la interacción social debido al confinamiento. Trabajos realizados en distintos países demostraron que la pandemia ha generado importantes trastornos del sueño. Con el objetivo de explorar si la pandemia afectó el sueño de los uruguayos, del 16 al 20 mayo del 2020 se realizó una encuesta anónima vía Web, a mayores de 18 años residentes en Uruguay (n =1137). Esta consistió en el Índice de Calidad de Sueño de Pittsburgh (ICSP), que es el cuestionario auto administrado más utilizado para este fin. El ICSP explora 7 dimensiones de sueño (calidad subjetiva, latencia, duración, eficiencia, perturbaciones, medicación y disfunción diurna), con un rango de puntaje de 0 a 21 (mayor puntuación, menor calidad de sueño), donde un ICSP mayor a 5 se considera una mala calidad de sueño. Los resultados mostraron que el ICSP promedio fue de 7,4 ± 4,0, presentando 63% de los encuestados un ICSP > 5. El ICSP fue mayor en mujeres (8,2 ± 4,0) que en hombres (6,4 ± 3,8; P < 0.001). El ICSP junto con otros parámetros relevados, sugieren que los residentes en Uruguay presentaron una mala calidad de sueño al comienzo de la pandemia.

The year 2020 will be remembered for the beginning of the COVID-19 pandemic, which has generated tragic consequences for personal and social health. In addition to deaths, infections and the fear of these, social interaction was considerably reduced due to confinement. Studies carried out in different countries showed that the pandemic has generated significant sleep disorders. With the aim of exploring whether the pandemic affected the sleep of Uruguayans, from May 16 to 20, 2020, an anonymous survey was carried out via the Web, to residents over 18 years of age in Uruguay (n = 1137). This consisted of the Pittsburgh Sleep Quality Index (PSQI), which is the most widely used self-administered questionnaire for this purpose. The PSQI explores 7 dimensions of sleep (subjective quality, latency, duration, efficiency, disturbances, medication, and daytime dysfunction), with a score range from 0 to 21 (higher score, lower sleep quality), where an ICSP greater than 5 it is considered a poor quality of sleep. The results showed that the average ICSP was 7.4 ± 4.0, with 63% of the respondents presenting an ICSP > 5. The ICSP was higher in women (8.2 ± 4.0) than in men (6.4 ± 3.8, P < 0.001). The ICSP, together with other parameters collected, suggest that residents of Uruguay had poor sleep quality at the beginning of the pandemic.

O ano de 2020 será lembrado pelo início da pandemia do COVID-19, que gerou consequências trágicas para a saúde pessoal e social. Além das mortes, das infecções e do medo destas, o convívio social foi consideravelmente reduzido devido ao confinamento. Trabalhos realizados em diferentes países mostraram que a pandemia gerou distúrbios significativos do sono. Com o objetivo de explorar se a pandemia afetou o sono dos uruguaios, de 16 a 20 de maio de 2020, foi realizada uma pesquisa anônima via Web, para maiores de 18 anos residentes no Uruguai (n = 1137). Este consistiu no Índice de Qualidade do Sono de Pittsburgh (ICSP), que é o questionário autoaplicável mais utilizado para esse fim. O ICSP explora 7 dimensões do sono (qualidade subjetiva, latência, duração, eficiência, distúrbios, medicação e disfunção diurna), com uma escala de pontuação de 0 a 21 (maior pontuação, menor qualidade do sono), onde um ICSP maior que 5 é considerado uma má qualidade de sono. Os resultados mostraram que o ICSP médio foi de 7,4 ± 4,0, com 63% dos entrevistados apresentando ICSP > 5. O ICSP foi maior nas mulheres (8,2 ± 4,0) do que nos homens (6,4 ± 3,8, P < 0,001). O ICSP, juntamente com outros parâmetros coletados, sugere que os residentes do Uruguai tinham má qualidade de sono no início da pandemia.

Passive and active DNA methylation and the interplay with genetic variation in gene regulation.

DNA methylation is an essential epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment are not fully understood. In this study we provide novel insights into the mechanistic relationships between genetic variation, DNA methylation and transcriptome sequencing data in three different cell-types of the GenCord human population cohort. We find that the association between DNA methylation and gene expression variation among individuals are likely due to different mechanisms from those establishing methylation-expression patterns during differentiation. Furthermore, cell-type differential DNA methylation may delineate a platform in which local inter-individual changes may respond to or act in gene regulation. We show that unlike genetic regulatory variation, DNA methylation alone does not significantly drive allele specific expression. Finally, inferred mechanistic relationships using genetic variation as well as correlations with TF abundance reveal both a passive and active role of DNA methylation to regulatory interactions influencing gene expression. DOI:http://dx.doi.org/10.7554/eLife.00523.001.