Biology subjects

Porcu, E.

Publications and source records attributed to Porcu, E..

13 recordsLinked to original sources

bioRxiv2022

Correction for participation bias in the UK Biobank reveals non-negligible impact on genetic associations and downstream analyses

While large-scale volunteer-based studies such as the UK Biobank (UKBB) have become the cornerstone of genetic epidemiology, the study participants are rarely representative of their target population. Here, we aim to evaluate the impact of non-random participation in the UKBB, and to pin down areas of research that are particularly susceptible to biases when using non-representative samples for genome-wide discovery. By comparing 14 harmonized characteristics of the UKBB participants to that of a representative sample, we derived a model for participation probability. We then conducted inverse probability weighted genome-wide association analyses (wGWA) on 19 UKBB traits. Comparing the output obtained from wGWA (Neffective=94,643 - 102,215) to standard GWA analyses (N=263,464 - 283,749), we assessed the impact of participation bias on three estimated quantities, namely 1) genotype-phenotype associations, 2) heritability and genetic correlation estimates and 3) exposure-outcome causal effect estimates obtained from Mendelian Randomization. Participation bias can lead to both overestimation (e.g., cancer, education) and underestimation (e.g., coffee intake, depression/anxiety) of SNP effects. Novel SNPs were identified in wGWA for 12 of the included traits, highlighting SNPs missed as a result of participation bias. While the impact of participation bias on heritability estimates was small (average change in h2: 1.5%, maximum: 5%), substantial distortions were present for genetic correlations (average absolute change in rg: 0.07, maximum: 0.31) and Mendelian Randomization estimates (average absolute change in standardized estimates: 0.04, maximum: 0.15), most markedly for socio-behavioural traits including education, smoking and BMI. Overall, the bias mainly affected the magnitude of effects, rather than direction. In contrast, genome-wide findings for more molecular/physical traits (e.g., LDL, SBP) exhibited less bias as a result of selective participation. Our results highlight that participation bias can distort genomic findings obtained in non-representative samples, and we propose a viable solution to reduce such bias. Moving forward, more efforts ensuring either sample representativeness or correcting for participation bias are paramount, especially when investigating the genetic underpinnings of behaviour, lifestyles and social outcomes.

genetics↗

bioRxiv2022

Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations

Despite the success of genome-wide association studies (GWASs) in identifying genetic variants associated with complex traits, understanding the mechanisms behind these statistical associations remains challenging. Several methods that integrate methylation, gene expression, and protein quantitative trait loci (QTLs) with GWAS data to determine their causal role in the path from genotype to phenotype have been proposed. Here, we developed and applied a multi-omics Mendelian randomization (MR) framework to study how metabolites mediate the effect of gene expression on complex traits. We identified 206 transcript-metabolite-trait causal triplets for 28 medically relevant phenotypes. Sixty-seven of these associations were missed by classical transcriptome-wide MR, which only uses gene expression and GWAS data. Among these, we identify biologically relevant pathways, such as between ANKH and calcium levels mediated by citrate and SLC6A12 and serum creatinine through modulation of the levels of the renal osmolyte betaine. We show that the signals missed by transcriptome-wide MR are found thanks to the gain in power allowed by integrating multiple omics-layer. Simulation analyses show that with larger molecular QTL studies and in case of mediated effects, our multi-omics MR framework outperforms classical MR approaches designed to detect causal relationships between single molecular traits and complex phenotypes.

genetics↗

bioRxiv2022

Omics-informed CNV calls reduce false positive rate and improve power for CNV-trait associations

Copy number variations (CNV) are believed to play an important role in a wide range of complex traits but discovering such associations remains challenging. Whilst whole genome sequencing (WGS) is the gold standard approach for CNV detection, there are several orders of magnitude more samples with available genotyping microarray data. Such array data can be exploited for CNV detection using dedicated software (e.g., PennCNV), however these calls suffer from elevated false positive and negative rates. In this study, we developed a CNV quality score that weights PennCNV calls (pCNV) based on their likelihood of being true positive. First, we established a measure of pCNV reliability by leveraging evidence from multiple omics data (WGS, transcriptomics and methylomics) obtained from the same samples. Next, we built a predictor of omics-confirmed pCNVs, termed omics-informed quality score (OQS), using only PennCNV software output parameters. Promisingly, OQS assigned to pCNVs detected in close family members was up to 35% higher than the OQS of pCNVs not carried by other relatives (P < 3.0-10-90), outperforming other scores. Finally, in an association study of four anthropometric traits in 89,516 Estonian Biobank samples, the use of OQS led to a relative increase in the trait variance explained by CNVs of up to 34% compared to raw pCNVs or previous quality scores. Overall, we put forward a flexible framework to improve any CNV detection method leveraging multi-omics evidence, applied it to improve PennCNV calls and demonstrated its utility by improving the statistical power for downstream association analyses.

bioinformatics↗

bioRxiv2021

Quantifying mediation between omics layers and complex traits

BackgroundHigh-dimensional omics datasets provide valuable resources to determine the causal role of molecular traits in mediating the path from genotype to phenotype. Making use of quantitative trait loci (QTL) and genome-wide association studies (GWASs) summary statistics, we developed a multivariable Mendelian randomization (MVMR) framework to quantify the connectivity between three omics layers (DNA methylome (DNAm), transcriptome and proteome) and their cascading causal impact on complex traits and diseases. ResultsEvaluating 50 complex traits, we found that on average 37.8% (95% CI: [36.0%-39.5%]) of DNAm-to-trait effects were mediated through transcripts in the cis-region, while only 15.8% (95% CI: [11.9%-19.6%]) are mediated through proteins in cis. DNAm sites typically regulate multiple transcripts, and while found to predominantly decrease gene expression, this was only the case for 53.4% across {approx} 47,000 significant DNAm-transcript pairs. The average mediation proportion for transcript-to-trait effects through proteins (encoded for by the assessed transcript or located in trans) was estimated to be 5.27% (95%CI: [4.11%-6.43%]). Notable differences in the transcript and protein QTL architectures were detected with only 22% of protein levels being causally driven by their corresponding transcript levels. Several regulatory mechanisms were hypothesized including an example where cg10385390 (chr1:8022505) increases the risk of irritable bowel disease by reducing PARK7 transcript and protein expression. ConclusionsThe proposed integrative framework identified putative causal chains through omics layers providing a powerful tool to map GWAS signals. Quantification of causal effects between successive layers indicated that molecular mechanisms can be more complex than what the central dogma of biology would suggest.

genomics↗

bioRxiv2021

Entering into a self-regulated learning mode prevents detrimental effect of feedback removal on memory

Recently, we provided causal evidence that self-regulated dopamine signaling enhanced long-term memory formation in the absence of any external feedback or reward (Ripolles et al., 2016, 2018) if a congruent meaning inferred from semantic context (DA-dependent learning), while DA-signals were absent if no congruent meaning could be inferred (DA-independent learning). Here, we investigated the interaction of self-regulated learning with externally-regulated DA-signalling by providing external performance feedback in the first or second half of trials. We found that removing feedback during DA-dependent learning lowered subsequent recognition rates a day later, whereas recognition remained high in the group which received feedback only in the second half. In contrast, feedback modestly enhanced recognition rates for both groups for DA-independent learning. Our findings suggest that external reinforcers can selectively impair DA-dependent memories if internal DA-dependent processes are not already established and highlights the relevance of self-regulated learning in education to support stable memory formation.

neuroscience↗

bioRxiv2020

The enrichment of breakpoints in late-replicating chromatin provides novel insights into chromoanagenesis mechanisms

The rise of pangenomic molecular assays allowed uncovering complex rearrangements named chromoanagenesis that were hypothesized to result from catastrophic shattering events. Constitutional cases have typically been reported individually preventing identification of common features and uncovering the mechanisms at play. We characterized 20 new chromoanagenesis and discovered yet undescribed features. While literature differentiates chromothripsis and its shattering event repaired through non-homologous end joining from chromoanasynthesis born to aberrant replicative processes, we identified shattered chromosomes repaired through a combination of mechanisms. In particular, three samples present with "rearrangement hubs" comprising a fragmented kilobase-long sequence threaded throughout the rearrangement. To assess the mechanisms at play, we merged our data with those of 20 published constitutional complex chromosomal rearrangement cases. We evaluated if the distribution of their 1032 combined breakpoints was distinctive using bootstrap simulations and found that breakpoints tend to keep away from haplosensitive genes suggesting selective pressure. We then compared their distribution with that of 13,310 and 468 breakpoints of cancer complex chromosomal rearrangements and constitutional simple rearrangement samples, respectively. Both complex rearrangement groups showed breakpoint enrichment in late replicating regions suggesting similar origins for constitutional and cancer cases. Simple rearrangement breakpoints but not complex ones were depleted from lamina-associated domains (LADs), possibly as a consequence of reduced mobility of DNA ends bound to lamina. The enrichment of breakpoints in late-replicating chromatin for both constitutional and cancer chromoanagenesis provides an orthogonal support to the premature chromosome condensation hypothesis that was put forward to explain chromoanagenesis.

genomics↗

bioRxiv2020

Reinstatement of cortical outcome representations during higher-order learning

Naturalistic learning scenarios are characterized by infrequent experience of external feedback to guide behavior. Higher-order learning mechanisms like second-order conditioning (SOC) may allow stimuli that were never experienced together with reinforcement to acquire motivational value. Despite its explanatory potential for real-world learning, surprisingly little is known about the neural mechanism underlying such associative transfer of value in SOC. Here, we used multivariate cross-session, cross-modality searchlight classification on functional magnetic resonance imaging data obtained from humans during SOC. We show that visual first-order conditioned stimuli (CS) reinstate cortical patterns representing previously paired gustatory outcomes in the lateral orbitofrontal cortex (OFC). During SOC, this OFC region showed increased functional covariation with amygdala, where neural pattern similarity between second-order CS and outcomes increased from early to late stages of SOC. Our data suggest a mechanism by which motivational value is conferred to stimuli that were never paired with reinforcement.

neuroscience↗

bioRxiv2020

The role of gene expression on human sexual dimorphism: too early to call

The genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS-associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits. To explore this scenario, we performed a genome-wide analysis of sex-specific whole blood RNA-seq eQTLs from 3,447 individuals. Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-specific cis-eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-specific eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-specific trait-associations. Power analyses using real eQTL- and causal effect sizes showed that millions of samples would be necessary to observe sex-specific trait associations that are fully driven by sex-specific cis-eQTLs. Compensatory effects may further hamper their detection. In line with this observation, we confirmed that the sex-specific trait-associations detected so far are not driven by sex-specific cis-eQTLs.

genetics↗

bioRxiv2019

Information-based taste maps in insular cortex are shaped by stimulus concentration

Taste processing is an essential ability in all animals signaling potential harm or benefit of ingestive behavior. Although the peripheral taste coding is well understood, current evidence for central taste processing remains contradictory. To address this issue, human participants judged pleasantness and intensity of low and high-concentration tastes (salty, sweet, sour, bitter) in two fMRI-experiments. High-resolution fMRI and multivariate pattern analysis were used to characterize taste-related informational content in human gustatory cortex (GC). Clusters within GC were narrowly tuned to specific tastants consistently across tasks. Importantly, taste concentrations completely altered the spatial layout of putative taste-specific maps with distinct, non-overlapping patterns for each taste category at different concentration levels. Together, our results point at population-level representations in human GC as a complex function of taste category and concentration.

neuroscience↗

bioRxiv2019

The human-specific BOLA2 duplication modifies iron homeostasis and anemia predisposition in chromosome 16p11.2 autism patients

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy number variations, one of the most common genetic causes of autism. These copy number polymorphic duplications are under positive selection and include 3-8 copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, P=4e-7, OR=5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, with 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, we found an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, P=1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The deletion and Bola2-deficient mice showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc protoporphyrin to heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo and its expansion has a potential adaptive role in protecting against iron deficiency.

genetics↗

bioRxiv2018

Unraveling the polygenic architecture of complex traits using blood eQTL meta-analysis

SummaryWhile many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear.\n\nTo identify these effects, we performed cis- and trans-expression quantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium.\n\nWe observed that cis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to use cis-eQTLs to pinpoint causal genes within susceptibility loci.\n\nIn contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology.\n\nWe observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.

genomics↗

bioRxiv2018

Mendelian Randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Genome-wide association studies (GWAS) identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs (eQTLs), indicating their potential involvement in the regulation of gene expression.\n\nHere, we propose an advanced transcriptome-wide summary statistics-based Mendelian Randomization approach (called TWMR) that uses multiple SNPs jointly as instruments and multiple gene expression traits as exposures, simultaneously.\n\nWhen applied to 43 human phenotypes it uncovered 2,369 genes whose blood expression is putatively associated with at least one phenotype resulting in 3,913 gene-trait associations; of note, 36% of them had no genome-wide significant SNP nearby in previous GWAS analysis. Using independent association summary statistics (UKBiobank), we confirmed that the majority of these loci were missed by conventional GWAS due to power issues. Noteworthy among these novel links is educational attainment-associated BSCL2, known to carry mutations leading to a mendelian form of encephalopathy. We similarly unraveled novel pleiotropic causal effects suggestive of mechanistic connections, e.g. the shared genetic effects of GSDMB in rheumatoid arthritis, ulcerative colitis and Crohns disease.\n\nOur advanced Mendelian Randomization unlocks hidden value from published GWAS through higher power in detecting associations. It better accounts for pleiotropy and unravels new biological mechanisms underlying complex and clinical traits.

genetics↗

bioRxiv2017

Audio-visual synchrony and spatial attention enhance processing of dynamic visual stimulation independently and in parallel: a frequency-tagging study

The neural processing of a visual stimulus can be facilitated by attending to its position or by a co-occurring auditory tone. Using frequency-tagging we investigated whether facilitation by spatial attention and audio-visual synchrony rely on similar neural processes. Participants attended to one of two flickering Gabor patches (14.17 and 17 Hz) located in opposite lower visual fields. Gabor patches further \"pulsed\" (i.e. showed smooth spatial frequency variations) at distinct rates (3.14 and 3.63 Hz). Frequency-modulating an auditory stimulus at the pulse-rate of one of the visual stimuli established audio-visual synchrony. Flicker and pulsed stimulation elicited stimulus-locked rhythmic electrophysiological brain responses that allowed tracking the neural processing of simultaneously presented stimuli. These steady-state responses (SSRs) were quantified in the spectral domain to examine visual stimulus processing under conditions of synchronous vs. asynchronous tone presentation and when respective stimulus positions were attended vs. unattended. Strikingly, unique patterns of effects on pulse- and flicker driven SSRs indicated that spatial attention and audiovisual synchrony facilitated early visual processing in parallel and via different cortical processes. We found attention effects to resemble the classical top-down gain effect facilitating both, flicker and pulse-driven SSRs. Audio-visual synchrony, in turn, only amplified synchrony-producing stimulus aspects (i.e. pulse-driven SSRs) possibly highlighting the role of temporally co-occurring sights and sounds in bottom-up multisensory integration.

neuroscience↗