Senior Researcher
Institute for Biomedicine
Luisa Foco is researcher in Biostatistics and Genetic Epidemiology. She obtained a degree in Biology at the University of Eastern Piedmont (1999), a master in Molecular medicine and Genetic Epidemiology at IUSS, Pavia (2001) and a PhD in Pharmacology and Pharmacoepidemiology at the University of Pavia (2006).
At the Eurac Research Institute for Biomedicine, she is senior researcher in the Biostatistics & Epidemiology group. She is interested in applying statistical and genetic epidemiological methods to investigate the genetics of complex traits. She actively collaborates with colleagues from the wet lab supporting them in study design and statistical analyses, and she’s passionate about communicating science to children.
She is PI of the study Roles of the RIOK1-PRMT5-MEP50-CENP-F axis in health, disease, and therapy (REFRESH) and she is involved in the Molecular profiling of uncontrolled and treatment resistant hypertension (the HyperProfile study).
Links
Google Scholar: https://scholar.google.com/citations?user=7bzFs-EAAAAJ&hl=it
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Meine Cookie EinstellungenFoco L
The seminar will present a case example where mendelian randomization was used to interpret the findings of a genetic association study and inform functional follow-up in laboratory.
It will also discuss the importance of formulating good research questions, deciding an appropriate study design, and interpreting the results in a meaningful way.
DOI: NA
Ghasemi-Semeskandeh D, König E, Foco L, Dordevic N, Gögele M, Rainer J, Ralser M, Acoba D,
Cristian Pattaro, Martin Gögele, Luisa Foco, Peter P. Pramstaller, Eva König, Johannes Rainer
Genome-wide association studies (GWAS) identified a locus on chromosome 4q21.1, spanning the Family With Sequence Similarity 47 Member E (FAM47E), Starch Binding Domain 1 (STBD1), Coiled-Coil Domain Containing 158 (CCDC158), and Shroom Family Member 3 (SHROOM3) genes, to be associated with kidney function markers. Functional studies implicated SHROOM3 as the effector gene, demonstrating its developmental role to guarantee podocyte barrier integrity. However, the locus has also been associated with other clinical traits, including electrolytes, hematological, cardiovascular, and neurological traits, not all of which can be easily traced to the regulation of kidney function. We therefore conducted a systematic analysis of the whole locus’ genetic profiles (haplotypes) to assess which phenotypic profiles they were associated with.
For the 4 genes, we reconstructed haplotypes spanning 71 exonic and intronic variants for 12,834 participants in the Cooperative Health Research in South Tyrol (CHRIS) study based on genotypes imputed on a local whole-exome sequencing (WES) reference panel. Haplotypes were tested for associations with 72 clinical traits, 170 serum metabolites, and 148 plasma protein concentrations, using linear regression models.
We identified 11 haplotypes with a population frequency between 2% and 24%. Compared with the most common haplotype, most haplotypes were associated with higher creatinine-based estimated glomerular filtration rate (eGFR) and lower serum magnesium levels. In addition, specific haplotypes were also associated with biologically diverse groups of traits, including albuminuria, blood pressure, red blood cell traits, carnitines, and amino acids. Cluster analysis highlighted the existence of distinct genetic profiles in which individuals with specific haplotypes presented with specific phenotypic and metabolic signatures.
The genetic variability of the FAM47E–SHROOM3 locus indicates the existence of population subgroups with distinct biomarker profiles.
DOI: 10.1016/j.ekir.2025.02.018
Foco L, De Bortoli M, Del Greco M F, Frommelt LS, Volani C, Riekschnitz DA, Motta BM, Fuchsberger C,
Cristian Pattaro, Martin Gögele, Luisa Foco, Peter P. Pramstaller, Marzia De Bortoli, Christian Fuchsberger, Diana Riekschnitz, Alessandra Rossini
Background
Cardiac desmosomes are specialized cell junctions responsible for cardiomyocytes mechanical coupling. Mutation in desmosomal genes cause autosomal dominant and recessive familial arrhythmogenic cardiomyopathy. Motivated by evidence that Mendelian diseases share genetic architecture with common complex traits, we assessed whether common variants in any desmosomal gene were associated with cardiac conduction traits in the general population.
Methods
We analysed data of N=4342 Cooperative Health Research in South Tyrol (CHRIS) study participants. We tested associations between genotype imputed variants covering the five desmosomal genes Desmoplakin (DSP), junction plakoglobin (JUP), plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2), and P-wave, PR, QRS, and QT electrocardiographic intervals, using linear mixed models. Functional annotation and interrogation of publicly available genome-wide association study resources implicated potential connection with antisense long non-coding RNAs (lncRNAs), DNA methylation sites, and complex traits. Causality was tested via two-sample Mendelian randomization (MR) analysis and validated with functional in vitro follow-up in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs).
Results
DSP variant rs2744389 was associated with QRS (P=3.5×10-6), with replication in the Microisolates in South Tyrol (MICROS) study (n=636; P=0.010). Observing that rs2744389 was associated with DSP-AS1 antisense lncRNA but not with DSP expression in multiple Genotype-Tissue Expression (GTEx) v8 tissues, we conducted two-sample Mendelian randomization analyses that identified causal effects of DSP-AS1 on DSP expression (P=6.33×10-5; colocalization posterior probability=0.91) and QRS (P=0.015). In hiPSC-CMs, DSP-AS1 expression downregulation through a specific GapmerR matching sequence led to significant DSP upregulation at both mRNA and protein levels.
Conclusions
The evidence that DSP-AS1 has a regulatory role on DSP opens the venue for further investigations on DSP-AS1’s therapeutic potential for conditions caused by reduced desmoplakin production.
DOI: 10.1007/s00439-025-02761-x
Ghasemi-Semeskandeh D, Foco L, Fujii R, Rainer J, Mohadeseh F, Ralser M, Domingues FS, Pramstaller PP,
Cristian Pattaro, Luisa Foco, Peter P. Pramstaller, Johannes Rainer
Genome-wide association studies (GWAS) generated thousands of loci associated with complex traits and diseases. However, to characterize of the pleiotropic, molecular and population genetic bounds of uncovered loci, investigations are conducted, that remain conceptually and practically separated. Also in the best case, such investigations proceed by one locus at a time. To address these limitations, we introduce an efficient and reproducible Snakemake pipeline for executing haplotype-based association analysis on GWAS-identified genetic loci, which is especially helpful in samples enriched with molecular omics data. Haplomics takes as input the genetic coordinates of each locus along with all available clinical and molecular phenotypes, the necessary covariates, and VCF genotype files, to reconstruct haplotypes and test them for associations with the phenotypes. The reconstructed haplotypes, the annotation of included variants, and association results are graphically displayed in an HTML report. We tested Haplomics in population-based study sample encompassing 391 traits, including 72 clinical markers, 171 serum metabolites, 148 plasma protein concentrations, and whole-exome sequencing (WES) imputed genotypes. We estimated WES-based haplotypes at 11 kidney function genetic loci from a GWAS and conducted association analyses throughout, identifying 19 significant associations after multiple testing correction. Haplomics is a scalable, easy-to-use and fast haplotype reconstruction and association pipeline that makes it possible to jointly conduct molecular and population-genetic characterization of multiple GWAS loci in unified analysis framework.
DOI: 10.1101/2025.06.12.25329492
Ghasemi-Semeskandeh D, Emmert D, König E, Foco L, Gögele M, Sarhan MS, Barin L, Fujii R,
Cristian Pattaro, Martin Gögele, Luisa Foco, Peter P. Pramstaller, David Emmert, Christian Fuchsberger, Eva König, Mohamed Sarhan
Chronic kidney disease (CKD) is a complex disease affecting >10% of the global population, with large between- and within-continent variability reflecting major environmental determinants. To identify molecular targets for treatment and prevention, genome-wide association study meta-analyses (GWAMAs) of CKD-defining traits have identified hundreds of genetic loci in aggregated population samples. However, while GWAMAs estimate the average allelic effect across studies, single population studies may be relevant to unravel specific mechanisms. To assess whether a study sample from a specific population could extend existing knowledge on kidney function genetics, we selected 147 kidney function relevant loci identified by a large GWAMA, assessing their association with the glomerular filtration rate estimated from serum creatinine (eGFRcrea) in 10,146 participants to the Cooperative Health Research In South Tyrol (CHRIS) study, conducted in an Alpine region where thyroid dysfunction is common. We identified associations with single nucleotide polymorphisms (SNPs) at 11 loci, showing up-to-5.4 times larger effect sizes than in the corresponding GWAMA, not explainable by allele frequency differences. Systematic mediation analysis across 70 quantitative traits identified serum magnesium and the activated partial thromboplastin time as partial mediators of the eGFRcrea associations at SHROOM3 and SLC34A1, respectively. Given that free triiodothyronine and thyroxine acted as effect modifiers across all loci, we conducted SNP-by-thyroid stimulating hormone (TSH) interaction analyses, identifying significant interactions at STC1: SNPs had larger effects on eGFRcrea at higher TSH levels, possibly reflecting stanniocalcin-1 autocrine and paracrine role. Individual population studies can help characterize genetic associations. The interplay between phenotypes at SHROOM3 and SLC34A1 and the role of thyroid function as a genetic effect modifier warrant further investigations.
DOI: 10.1371/journal.pone.0323057
De Bortoli M, Foco L, Frommelt LS, Riekschnitz DA, Volani C, Motta BM, Fuchsberger C, Pramstaller PP,
Cristian Pattaro, Luisa Foco, Peter P. Pramstaller, Marzia De Bortoli, Christian Fuchsberger, Diana Riekschnitz, Alessandra Rossini
Background: Desmosomal genes are established as definitive genes for Arrhythmogenic Cardiomyopathy (ACM). The desmoplakin encoding gene, DSP, is amongst the most frequently mutated genes in ACM patients. While rare genetic variants within desmosomal genes can cause ACM, common variants might also affect cardiac conduction traits in the general population.
Purpose: 1) To explore the association between common genetic variants in ACM desmosomal genes (DSC2, DSG2, PKP2, JUP, DSP) and cardiac conduction traits. 2) To investigate the effect of a lncRNA, identified from downstream analyses, on DSP gene expression.
Methods: P-wave, PR, QRS and QT intervals were measured using standard 12-lead electrocardiograms (ECG) in 4295 participants to the Cooperative Health Research in South Tyrol (CHRIS) study (data release 2). Samples were genotyped using the Illumina HumanOmniExpressExome array and imputed on the 1000 Genome Phase 1 panel. We conducted a genetic association study on 3458 variants within the linkage disequilibrium blocks that encompass desmosomal genes, assuming an additive genetic model, at 1.9x10-4 statistical significance. Mendelian Randomization (MR) analyses integrating ECG traits and Genotype-Tissue Expression (GTEx) database transcription levels were performed. A specific GapmeR was used to downregulate the antisense RP3-512B11.3 lncRNA expression in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). hiPSC-CMs lysates were analyzed by digital droplet PCR and Wes™ immunoassay system.
Results: The rs2744389 variant in DSP gene is associated with a shorter QRS interval (-1.10 ms per effect allele copy; p=3.5x10-6). In the GTEx database, rs2744389 is identified as an expression quantitative trait locus for the antisense lncRNA. MR results support a causal effect of the lncRNA on QRS. To assess the hypothesis that the lncRNA regulates DSP gene expression, we identified a Gapmer able to downregulate the lncRNA expression by approximately 60% in hiPSC-CMs. The lncRNA downregulation led to a significant increase of DSP expression, both at mRNA and protein level, compared to hiPSC-CMs treated with a negative control Gapmer (DSP/RPP30: 16.39±3.32 vs 11.84±1.79; p=0.0313), (Desmoplakin/total protein: 2.44±0.29 vs 1.66±0.11; p=0.0156).
Conclusions: Starting with the identification of an association between a common genetic variant in DSP gene and a significantly shorter QRS interval in a general population sample, we further unrevealed a new mechanism regulating DSP expression through an antisense lncRNA. While requiring further evidence, these findings might pave the way to a potentially novel therapeutic approach for DSP mutations carriers characterized by desmoplakin protein deficit, as for example patients affected by ACM, but also by dilated cardiomyopathy, cardiocutaneous diseases such as the Carvajal syndrome, and some cancer conditions.
DOI: 10.1093/cvr/cvae088.109
Noce D, Foco L, Orth-Höller D, König E, Barbieri G, Pietzner M, Ghasemi-Semeskandeh D, Coassin S,
Cristian Pattaro, Martin Gögele, Luisa Foco, Peter P. Pramstaller, Alessandro De Grandi, Christian Fuchsberger, Eva König
Projekt: PACE: Partnership to Accelerate Covid-19 rEsearch in South Tyrol
Complement is a fundamental innate immune response component. Its alterations are associated with severe systemic diseases. To illuminate the complement’s genetic underpinnings, we conduct genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways in the Cooperative Health Research in South Tyrol study (n = 4,990).We identify seven loci, encompassing 13 independent, pathway-specific variants located in or near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining up to 74% of complement pathways’ genetic heritability and implicating long-range haplotypes associated with LP at MBL2. Two-sample Mendelian randomization analyses, supported by transcriptome- and proteome-wide colocalization, confirm known causal pathways, establish within-complement feedback loops, and implicate causality of ABO on LP and of CFHR2 and C7 on AP. LP causally influences collectin-11 and KAAG1 levels and the risk of mouth ulcers. These results build a comprehensive resource to investigate the role of complement in human health.
DOI: 10.1016/j.celrep.2023.113611
Young WJ, van der Most PJ, Bartz TM, Bos MM, Biino G, Duong T, Foco L, Lominchar JT,
Cristian Pattaro, Martin Gögele, Luisa Foco, Peter P. Pramstaller, Alessandro De Grandi, Christian Fuchsberger
Background: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability.
Methods and results: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10-8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6).
Conclusions: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.
DOI: 10.1161/JAHA.123.034760
Hantikainen E, Weichenberger CX, Dordevic N, Verri Hernandes V, Foco L, Gögele M, Melotti R, Pattaro C,
Cristian Pattaro, Christian Weichenberger, Martin Gögele, Roberto Melotti, Luisa Foco, Peter P. Pramstaller, Essi Hantikainen
Identifying biomarkers able to discriminate individuals on different health trajectories is crucial to understand the molecular basis of age-related morbidity. We investigated multi-omics signatures of general health and organ-specific morbidity, as well as their interconnectivity. We examined cross-sectional metabolome and proteome data from 3,142 adults of the Cooperative Health Research in South Tyrol (CHRIS) study, an Alpine population study designed to investigate how human biology, environment, and lifestyle factors contribute to people's health over time. We had 174 metabolites and 148 proteins quantified from fasting serum and plasma samples. We used the Cumulative Illness Rating Scale (CIRS) Comorbidity Index (CMI), which considers morbidity in 14 organ systems, to assess health status (any morbidity vs. healthy). Omics-signatures for health status were identified using random forest (RF) classifiers. Linear regression models were fitted to assess directionality of omics markers and health status associations, as well as to identify omics markers related to organ-specific morbidity. Next to age, we identified 21 metabolites and 10 proteins as relevant predictors of health status and results confirmed associations for serotonin and glutamate to be age-independent. Considering organ-specific morbidity, several metabolites and proteins were jointly related to endocrine, cardiovascular, and renal morbidity. To conclude, circulating serotonin was identified as a potential novel predictor for overall morbidity.
DOI: 10.1038/s41598-024-75627-3
Ghasemi-Semeskandeh D, König E, Foco L, Dordevic N, Gögele M, Rainer J, Ralser M, Acoba D,
Cristian Pattaro, Martin Gögele, Luisa Foco, Peter P. Pramstaller, Eva König, Johannes Rainer
Background/objectives: Genome-wide association studies identified a chromosome 4q21.1 locus
spanning FAM47E, STBD1, CCDC158, and SHROOM3, prominently associated with kidney function
markers but also with electrolytes, hematological and cardiovascular traits. Functional studies linked
SHROOM3, encoding an actin-binding protein involved in cell shaping, with kidney damage. However,
systematic explorations of functional variants of all genes at the locus are lacking. We thus conducted
phenome-wide, metabolomic and proteomic analyses of exonic haplotypes spanning the four genes.
Methods: We reconstructed haplotypes for 12,834 individuals of the Cooperative Health Research in
South Tyrol (CHRIS) study, following genotype imputation from a whole-exome sequencing reference
panel of a 3422 CHRIS sample subset. Haplotypes, including 146 exonic and intronic variants over the
four genes, were tested for association with 74 serum, urine, and anthropometric traits, 172 serum
metabolites, and 148 plasma proteins concentrations using linear models.
Results: The 11 identified haplotypes (frequency: 2% to 24%) showed both shared and specific
characteristics. Compared to the most common haplotype, most haplotypes were jointly associated with
kidney function and serum magnesium levels. The second most common haplotype (12% frequency)
was associated with better kidney function and lower dodecanoyl-, hydroxyvaleryl- and tiglyl-carnitine
concentrations. A haplotype of 4% frequency was associated with better kidney function and lower
hematological marker levels. A haplotype of 2% frequency was associated with lower magnesium,
glutamine, and putrescine levels. Cluster analysis revealed six distinct trait groups and two distinct
haplotype groups.
Conclusion: FAM47E-SHROOM3 functional haplotypes exhibit marked pleiotropic effects and identify
population subgroups with distinct biomarker profiles.
DOI: 10.1101/2024.03.22.24304731
Benzoni P, Arici M, Giannetti F, Cospito A, Prevostini R, Volani C, Fassina L, Rosato-Siri MD,
Aim: Striatin (Strn) is a scaffold protein expressed in cardiomyocytes (CMs) and alteration of its expression are described in various cardiac diseases. However, the alteration underlying its pathogenicity have been poorly investigated.
Methods: We studied the role(s) of cardiac Strn gene (STRN) by comparing the functional properties of CMs, generated from Strn-KO and isogenic WT mouse embryonic stem cell lines.
Results: The spontaneous beating rate of Strn-KO CMs was faster than WT cells, and this correlated with a larger fast INa conductance and no changes in If. Paced (2-8 Hz) Strn-KO CMs showed prolonged action potential (AP) duration in comparison with WT CMs and this was not associated with changes in ICaL and IKr. Motion video tracking analysis highlighted an altered contraction in Strn-KO CMs; this was associated with a global increase in intracellular Ca2+, caused by an enhanced late Na+ current density (INaL) and a reduced Na+/Ca2+ exchanger (NCX) activity and expression. Immunofluorescence analysis confirmed the higher Na+ channel expression and a more dynamic microtubule network in Strn-KO CMs than in WT. Indeed, incubation of Strn-KO CMs with the microtubule stabilizer taxol, induced a rescue (downregulation) of INa conductance toward WT levels.
Conclusion: Loss of STRN alters CMs electrical and contractile profiles and affects cell functionality by a disarrangement of Strn-related multi-protein complexes. This leads to impaired microtubules dynamics and Na+ channels trafficking to the plasma membrane, causing a global Na+ and Ca2+ enhancement.
DOI: 10.1111/apha.14160
Noce D, Foco L, Orth-Höller D, König E, Barbieri G, Pietzner M, Coassin S, Fuchsberger C,
Cristian Pattaro, Martin Gögele, Luisa Foco, Peter P. Pramstaller, Alessandro De Grandi, Christian Fuchsberger, Eva König
Projekt: PACE: Partnership to Accelerate Covid-19 rEsearch in South Tyrol
Background: Complement is a fundamental part of the innate immune response. Its alterations are associated with severe systemic diseases.
Methods: To illuminate the complement’s genetic underpinnings, we conducted genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways using serum samples, stored at –80_C since the day of collection, analyzed with the WIESLAB_ complement system screen kit (SVAR, Malmö, formerly Wieslab AB, Lund, Sweden) according to manufacturers’ instructions in the Cooperative Health Research in South Tyrol (CHRIS) study (n=4990).
Results: We identified 7 loci that included 13 independent, pathway-specific variants (p<5_10-8) located in or near complement (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining 12%, 18% and 73% of CP, AP and LP’s genetic heritability, respectively. Variants were associated with inflammatory, autoimmune and coagulation disorders and >400 proteins. Transcriptome- and proteome-wide colocalization analyses combined with two-sample Mendelian randomization confirmed known causal pathways, established within-complement feedback loops, and implicated causality of ABO on LP and of CFHR2 and C7 on AP. LP showed causal effects on collectin-11 and KAAG1 levels and mouth ulcers’ risk. Conclusion: These results build a comprehensive resource to investigate the role of complement on human health.
DOI: 10.1016/j.imbio.2023.152626
