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Irene Gonzalez,1 Rocio Polvillo,1,2 Maximiliano Ruiz-Galdon,1 Armando Reyes-Engel,1 Jose Luis Royo1 1Department of Surgery, Biochemistry and Immunology School of Medicine, University of Malaga, Malaga, Spain; 2Centro Andaluz de Biología del Desarrollo, Seville, 41013, SpainCorrespondence: Armando Reyes-Engel; Jose Luis Royo Tel +34 952131531; +34 952136655Email engel@uma.es; jlroyo@uma.esPurpose: Tryptophan is the only precursor of serotonin, the hormone which helps regulate key human functions such as appetite, memory, mood, and sexual behavior. Connections have been identified between serotonin system dysfunction and the molecular etiology and treatment of mood disorders in a wide range of studies. Proposals have been put forward to co-administer tryptophan supplementation together with serotonin reuptake inhibitors in major depression patients, and also to exploit the sub-therapeutic depressive status in healthy populations. The reported responses, however, have been very dissimilar and this uneven effect may largely be explained by interindividual genetic differences.Materials and Methods: We studied mood change in 138 healthy subjects using both Goldberg’s General Health Questionnaire and the Profile of Mood States Questionnaire to determine the effects of a daily supplementation of 1g of tryptophan or placebo. Buccal DNA samples were provided and TPH1 (rs1800532), MAOA (rs3788862 and rs979605), MAOB (rs3027452), and COMT (rs6269 and rs4680) variants were genotyped.Results: MAOB rs3027452 was equally associated with tryptophan supplementation efficacy in the depression subscales of both questionnaires (ΔT-Score.D; ΔT-Score.TMD and ΔPOMS.D p-values < 0.01).Conclusion: Here we provide evidence that tryptophan supplementation has an uneven effect on mood improvement in the general population.Keywords: tryptophan, serotonin, 5-HT, mood, pharmacogenetics, monoamine oxidase

Background: Hepatic encephalopathy is a major complication of cirrhosis and is associated with a poor prognosis. Objective: To identify mutations in the gene sequence for glutaminase in humans that could be responsible for the development of hepatic encephalopathy in patients with cirrhosis. Design: Cohort study. Setting: Outpatient clinics in 6 Spanish hospitals. Patients: 109 consecutive patients with cirrhosis in the estimation cohort, 177 patients in the validation cohort, and 107 healthy control participants. Measurements: Patients were followed every 3 or 6 months until the development of hepatic encephalopathy or liver transplantation, death, or the end of the study. Results: The genetic analyses showed that glutaminase TACC and CACC haplotypes were linked to the risk for overt hepatic encephalopathy. Mutation scanning of the glutaminase gene identified a section in the promoter region where base pairs were repeated (a microsatellite). Over a mean follow-up of 29.6 months, hepatic encephalopathy occurred in 28 patients (25.7%) in the estimation cohort. Multivariable Cox models were used to determine the following independent predictors: Child-Turcotte-Pugh stage (hazard ratio [HR], 1.6 [95% CI, 1.29 to 1.98]; P = 0.001), minimal hepatic encephalopathy (HR, 3.17 [CI, 1.42 to 7.09]; P = 0.006), and having 2 long alleles of the microsatellite (HR, 3.12 [CI, 1.39 to 7.02]; P = 0.006). The association between 2 long alleles of the microsatellite and overt hepatic encephalopathy was confirmed in a validation cohort (HR, 2.1 [CI, 1.17 to 3.79]; P = 0.012). Functional studies showed higher luciferase activity in cells transfected with the long form of the microsatellite, which suggests that the long microsatellite enhances glutaminase transcriptional activity. Limitation: Other genes and allelic variants might be involved in the clinical expression of hepatic encephalopathy. Conclusion: This study identifies a genetic factor that is associated with development of hepatic encephalopathy in patients with cirrhosis. Primary Funding Source: Instituto de Salud Carlos III, Spanish Ministry of Health. [ABSTRACT FROM AUTHOR]

Background: On its physiological cellular context, PTTG1 controls sister chromatid segregation during mitosis. Within its crosstalk to the cellular arrest machinery, relies a checkpoint of integrity for which gained the over name of securin. PTTG1 was found to promote malignant transformation in 3T3 fibroblasts, and further found to be overexpressed in different tumor types. More recently, PTTG1 has been also related to different processes such as DNA repair and found to trans-activate different cellular pathways involving c-myc, bax or p53, among others. PTTG1 over-expression has been correlated to a worse prognosis in thyroid, lung, colorectal cancer patients, and it can not be excluded that this effect may also occur in other tumor types. Despite the clinical relevance and the increasing molecular characterization of PTTG1, the reason for its up-regulation remains unclear.Method: We analysed PTTG1 differential expression in PC-3, DU-145 and LNCaP tumor cell lines, cultured in the presence of the methyl-transferase inhibitor 5-Aza-2'-deoxycytidine. We also tested whether the CpG island mapping PTTG1 proximal promoter evidenced a differential methylation pattern in differentiated thyroid cancer biopsies concordant to their PTTG1 immunohistochemistry status. Finally, we performed whole-genome LOH studies using Affymetix 50 K microarray technology and FRET analysis to search for allelic imbalances comprising the PTTG1 locus.Conclusion: Our data suggest that neither methylation alterations nor LOH are involved in PTTG1 over-expression. These data, together with those previously reported, point towards a post-transcriptional level of misregulation associated to PTTG1 over-expression. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) has a high heritable component characteristic of complex diseases, yet many of the genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may be helpful to understand the underlying biology of the disease., Methods: We performed a meta-analysis of GWAS of CSF Aβ42 and PET measures combining six independent cohorts (n=2,076). Due to the opposite effect direction of Aβ phenotypes in CSF and PET measures, only genetic signals in the opposite direction were considered for analysis (n=376,599). Polygenic risk scores (PRS) were calculated and evaluated for AD status and amyloid endophenotypes. We then searched the CSF proteome signature of brain amyloidosis using SOMAscan proteomic data (Ace cohort, n=1,008) and connected it with GWAS results of loci modulating amyloidosis. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n=13,409) and PET (n=13,116). This combined approach enabled the identification of overlapping genes and proteins associated with amyloid burden and the assessment of their biological significance using enrichment analyses., Results: After filtering the meta-GWAS, we observed genome-wide significance in the rs429358- APOE locus and nine suggestive hits were annotated. We replicated the APOE loci using the large CSF-PET meta-GWAS and identified multiple AD-associated genes as well as the novel GADL1 locus. Additionally, we found a significant association between the AD PRS and amyloid levels, whereas no significant association was found between any Aβ PRS with AD risk. CSF SOMAscan analysis identified 1,387 FDR-significant proteins associated with CSF Aβ42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was very poor (n=35). The enrichment analysis of overlapping hits strongly suggested several signalling pathways connecting amyloidosis with the anchored component of the plasma membrane, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis., Conclusions: The strategy of combining CSF and PET amyloid endophenotypes GWAS with CSF proteome analyses might be effective for identifying signals associated with the AD pathological process and elucidate causative molecular mechanisms behind the amyloid mobilization in AD., Competing Interests: Competing interests All authors declare that the research was conducted in the absence of any conflict of interest.

Alzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous genome wide association study, using a new pipeline design to identify novel potential drugs. With this approach, ribonucleoside-diphosphate reductase gene (RRM2B) emerged as a candidate target and its inhibitor, 2', 2'-difluoro 2'deoxycytidine (gemcitabine), as a potential pharmaceutical drug against Alzheimer's disease. We functionally verified the effect of inhibiting the RRM2B homolog, rnr-2, in an Alzheimer's model of Caenorhabditis elegans, which accumulates human Aβ1-42 peptide to an irreversible paralysis. RNA interference against rnr-2 and also treatment with 200 ng/ml of gemcitabine, showed an improvement of the phenotype. Gemcitabine treatment increased the intracellular ATP level 3.03 times, which may point to its mechanism of action. Gemcitabine has been extensively used in humans for cancer treatment but at higher concentrations. The 200 ng/ml concentration did not exert a significant effect over cell cycle, or affected cell viability when assayed in the microglia N13 cell line. Thus, the inhibitory drug of the RRM2B activity could be of potential use to treat Alzheimer's disease and particularly gemcitabine might be considered as a promising candidate to be repurposed for its treatment., Competing Interests: Conflicts of interest AMBL, MSI, CV, JLR, and MJM signed as authors of a patent application P201830955. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Background & Aims: It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV)., Objective: To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype., Patients and Methods: In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0., Results: It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition., Conclusions: Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Carmen Martín-Sierra, María José Bravo, María Eugenia Sáez, Itziar De Rojas, Marta Santos, Jesica Martín-Carmona, Anaïs Corma-Gómez, Alejandro González-Serna, José Luis Royo, Juan A Pineda, Antonio Rivero, Antonio Rivero-Juárez, Juan Macías, Luis Miguel Real., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Studying host-pathogen interactions at a molecular level has always been technically challenging. Identifying the different biochemical and genetic pathways involved in the different stages of infection traditionally require complex molecular biology tools and often the use of costly animal models. In this chapter, we illustrate a complementary approach to address host-pathogen interactions, taking advantage of the natural interindividual genetic diversity. The application of genetic association studies allows us to identify alleles involved in infection progression or resistance. Thus, this strategy may be useful to unravel new molecular pathways underlying host-pathogen interactions. Here we present the general steps that might be followed to plan, execute, and analyze a population-based study in order to identify genetic variants affecting human exposition to pathogens., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP., Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology., Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells., Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation., Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 10 7 single-nucleotide polymorphisms performed on Alzheimer's disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ 1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin's effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.

Some HIV controllers experience immunologic progression with CD4 + T cell decline. We aimed to identify genetic factors associated with CD4 + T cell lost in HIV controllers . A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia., Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention., Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022., Exposures: Genetically determined modifiable risk factors., Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors., Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50])., Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

Genome variations contribute to the vast majority of interindividual differences and may decisively influence sports capability. This study was conceived as a means of finding out when exactly polymorphisms start being physically discriminative. The polymorphisms we studied were two of the best characterized ones: ACE I/D and ACTN3 R577X. These germline variants were determined in a cohort of 200 healthy volunteers from the university environment who underwent a series of physical evaluations that included a Cooper test, a 20-meter sprint test and a vertical jump test. Initially, no statistical association was found because the genetic effect was masked by those subjects with sedentary lifestyles. But when only physically active volunteers were considered, the ACE and ACTN3 genotypes were found to have an impact on heart rate after the Cooper test (p-value = 0.033 and 0.032 respectively) and ACTN3 was found to correlate with the total distance covered in the same test (p-value = 0.051). This can therefore be considered a paradigmatic example in which the environment might hide the genetic effect, with genotypic differences arising only upon training., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit ( p = 4.22 × 10 -20 ) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.

Importance: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly., Objective: To determine whether rare missense variants on APOE are associated with AD risk., Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021., Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression., Results: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers., Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., (© 2022. The Author(s).)

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region ( LZTFL1, SLC6A20 ) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

Alzheimer's disease is the most common cause of dementia worldwide, and longitudinal studies are crucial to find the factors affecting disease development. Here, we describe a novel initiative from southern Spain designed to contribute in the identification of the genetic component of the cognitive decline of Alzheimer's disease patients. The germline variant rs9320913 is a C>A substitution mapping within a gene desert. Although it has been previously associated to a higher educational achievement and increased fluid intelligence, its role on Alzheimer's disease risk and progression remains elusive. A total of 407 subjects were included in the study, comprising 153 Alzheimer disease patients and 254 healthy controls. We have explored the rs9320913 contribution to both Alzheimer disease risk and progression according to the Mini-Mental State Exams. We found that rs9320913 maps within a central nervous system lincRNA AL589740.1. eQTL results show that rs9320913 correlated with the brain-frontal cortex (beta = -0.15, p value = 0.057) and brain-spinal cord (beta of -0.23, p value = 0.037). We did not find rs9320913 to be associated to AD risk, although AA patients seemed to exhibit a less pronounced Mini-Mental State Exam score decline., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2021 Lidia Lopez-Gutierrez et al.)

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [β AVROH (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10 -5 ; β FROH (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10 -16 ). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10 -4 ), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.

A key advance in our understanding of gene regulation came with the finding that the genome undergoes three-dimensional nuclear folding in a genetically determined process. This 3D conformation directly influences the association between enhancers and their target promoters. This complex interplay has been proven to be essential for gene regulation, and genetic variants affecting this process have been associated to human diseases. The development of new technologies that quantify these DNA interactions represented a revolution in the field. High throughput techniques like HiC provide a general picture of chromatin topology. However, they often lack resolution to evidence subtle effects that single nucleotide polymorphisms exert over the contacts between cis-regulatory regions and target promoters. Here we propose a cost-efficient approach to perform allele-specific chromatin conformation analysis. As a proof of concept, we analyzed the impact of a common deletion mapping between SIRPB1 promoter and one of its downstream enhancers., (Copyright © 2020. Published by Elsevier B.V.)

Toll-like receptor 2 (TLR2) plays a key role in innate immune response recognizing molecular patterns expressed by pathogens. rs111200466 is a TLR2 promoter insertion/deletion polymorphism with contradictory data about its role in human immunodeficiency virus type 1 (HIV-1) infection. We analyzed rs111200466 in HIV-1 disease progression and showed a correlation with a faster progression to the CD4+ < 200 cells/μL outcome for deletion allele carriers (Cox regression analysis: hazard ratio, 2.4 [95% confidence interval, 1.4-4]; P = .001). When naive patients with CD4+ < 200 cells/μL started antiretroviral treatment, rs111200466-deletion carriers showed a trend toward a slower, recovery rate (time required to reach CD4+ > 350 cells/μL; Cox P = .36). Our data suggest rs111200466 as a prognosis factor for HIV-1 disease progression., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: The Brown trout is a salmonid species with a high commercial value in Europe. Life history and spawning behaviour include resident (Salmo trutta m. fario) and migratory (Salmo trutta m. trutta) ecotypes. The main objective is to apply RNA-seq technology in order to obtain a reference transcriptome of two key tissues, brain and muscle, of the riverine trout Salmo trutta m. fario. Having a reference transcriptome of the resident form will complement genomic resources of salmonid species., Data Description: We generate two cDNA libraries from pooled RNA samples, isolated from muscle and brain tissues of adult individuals of Salmo trutta m. fario, which were sequenced by Illumina technology. Raw reads were subjected to de-novo transcriptome assembly using Trinity, and coding regions were predicted by TransDecoder. A final set of 35,049 non-redundant ORF unigenes were annotated. Tissue differential expression analysis was evaluated by Cuffdiff. A False Discovery Rate (FDR) ≤ 0.01 was considered for significant differential expression, allowing to identify key differentially expressed unigenes. Finally, we have identified SNP variants that will be useful tools for population genomic studies.

Objectives: An increasing evidence suggests hypertension (HTN) could be linked to cognitive impairment and incident Alzheimer's disease (AD). The precise mechanisms linking HTN and AD are not well-known. The aim of this study was to assess the putative association between HTN and AD., Methods: We assessed in patients with AD associations between HTN and demographic and clinical data, vascular risk factors, treatments, APOE genotypes, brain white matter hyperintensities (WMH), and medial temporal atrophy (MTA) in multivariate analysis of covariance., Results: We studied 92 patients with AD (mean ± SD age: 72.12 ± 6.91; women: 66.30%). Patients with HTN had significantly worse cognitive and functional status and higher frequency and severity of neuropsychiatric symptoms (P = .010). Magnetic resonance imaging analyzes showed significant increases in WMH (P = .018) and in MTA (P = .012) in patients with AD with HTN compared with those without HTN., Conclusions: Neuroimaging burden (MTA and higher degree of severity of WMH) among patients with AD and HTN are associated with the impaired cognitive function and neuropsychiatric symptoms., (© 2020 John Wiley & Sons Ltd.)

Objectives: Complement C3d receptor 2 (CR2) is the main receptor for complement protein C3d and plays an important role in adaptive immune responses. CR2 genetic variants are associated with susceptibility to systemic lupus erythematosus as well as to HIV-1 infection. In addition, CR2 function can be subverted by HIV-1 for an efficient entry into target cells; in a process known as antibody-dependent enhancement of viral infection. We sought to determine the association between CR2 gene variants with HIV-1 acquisition after vaccination with recombinant gp120 protein (Vax004 clinical trial)., Design and Methods: This is a retrospective cross-sectional study, comprising male volunteers of European ancestry including infected (n = 273) and uninfected (n = 402) vaccinees and placebo, who were genotyped for three single nucleotide polymorphisms (SNPs) in the CR2 gene region., Results: An interaction was observed between the baseline sexual behavior and the SNP rs3813946 for higher risk of infection in vacinees (interaction term P = 0.02). This SNP was associated with increased susceptibility to HIV-1 infection after vaccination in volunteers with low behavioral risk odds ratio (95% confidence interval): 5.5 (1.4-21.7) P = 0.006 but not vaccinees with high behavioral risk or volunteers given placebo (P = 0.7). Moreover, CR2 genotype was strongly associated with the rate of HIV-1 acquisition after vaccination in low-risk volunteers [hazard odds ratio (95% confidence interval): 3.3 (1.6-7.0), P = 0.001]., Conclusion: The current study suggests that CR2 may play a role in HIV-1 acquisition after vaccination with rgp120 proteins.

Background: Monoamine oxidase (MAO) activity has been traditionally implicated in blood pressure through its effects on biogenic amine levels such as catecholamines, serotonin, and dopamine. Nowadays, this role is considered relegated to side-effects such as orthostatic hypotension and/or hypertensive crisis derived from MAO-inhibitory treatments in patients with psychiatric disease., Methods: In the present work we have found an association between a polymorphic variant of MAOB gene and arterial hypertension in obese hypogonadic patients. The study cases comprised a series of 219 nondiabetic males with a body mass index ≥30 kg/m 2 and aged <45 years. Hypogonadism was defined as subnormal testosterone concentrations, when free testosterone values ranged <65 pg/ml., Results: MAOB rs3027452-A allele carriers were significantly over-represented among hypertensive (HT) patients (25.49%) in comparison to either the non-HT patients (10%, OR = 3.079 CI 95 [1.364-6.952], p = .005, Chi-square test) and the control population series of nonobese nor hypogonadic males (also 10%, p = .003 Chi-square test). Upon adjusted, an independent association was shown with the hypogonadic group with hypertension when compared with nonhypertensive hypogonadics (Beta = 3.653, p = .005). When quantitative analysis was performed, hypertensive patients harboring rs3027452-A allele showed higher systolic blood pressure values (p = .038, Mann-Whitney U-test) as well as an increased Systolic-Diastolic range despite following HT treatment (∆mmHg 54 vs. 48 for rs3027452-A and rs3027452-G respectively, p-value .019, Mann-Whitney U-test). Previous studies on MAOB revealed that rs3027452-A allele has been correlated to a lower activity of the enzyme, what gives a functional evidence over our observation., Conclusion: If this result could be extrapolated to other hypertensive patient groups, it would implicate a review of the markers and therapeutic targets on human hypertension., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways., Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets., Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444., Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Obesity has been associated with increased risk of presenting hypogonadism. Free testosterone (FT) is the fraction of testosterone that carries out the biological function of testosterone, and is determined from total testosterone (TT) and sex-hormone binding globulin (SHBG) levels. We aimed to study the SHBG polymorphism rs1799941 in a cohort of young non-diabetic obese males to unravel the possible implication of this polymorphism in obesity-related hypogonadism., Methodology: 212 young (<45 years) non-diabetic obese (BMI ≥ 30 kg/m 2 ) males participated in this study. Subjects were classified according to TT and FT levels in: Eugonadal ( n = 55, TT > 3.5 ng/mL and FT ≥ 70 pg/mL; EuG), normal FT hypogonadism ( n = 40, TT < 3.5 and FT ≥ 70 pg/mL; normal FT HG) and hypogonadism ( n = 117, TT < 3.5 ng/mL and TL < 70 pg/mL; HG). The SHBG rs1799941 polymorphism (GG/GA/AA) was analyzed using the Taqman Open Array (Applied biosystem)., Results: The rs1799941 frequencies were different among the groups. Higher proportion of the allele (A) was found in HG, compared to EuG and normal FT HG. Among the genotypes, the rare homozygous (AA) were found in the normal FT HG group and higher levels of serum SHBG and lower of FT were observed. The presence of the allele A was related (according to lineal regression models) to an increased of SHBG levels ((GA) β = 3.28; (AA) β = 12.45) and a decreased of FT levels ((GA) β = -9.19; (AA) β = -18.52). The presence of the allele (A) increased the risk of presenting HG compared to normal FT HG (OR = 2.54)., Conclusions: The rs1799941 of the SHBG gene can partially determine the presence of obesity-related hypogonadism in young non-diabetic males and whether these subjects have normal FT HG.

Magnetic nanoparticles (MNPs) represent one of the greatest promises for the development of a new generation of diagnostic agents for magnetic resonance imaging, with improved specificity and safety. Indeed, during the last decade the number of studies published in this field has grown exponentially. However, the clinical translation achieved so far has been very limited. This situation is likely related to the fact that most studies are focused on the in vitro characterization of these new nanomaterials, and very few provide an exhaustive in vivo characterization, where key aspects, such as pharmacokinetics, bioavailability, and, most importantly, toxicity, are properly evaluated. In this work, we propose a protocol for the comprehensive assessment of the toxicity of MNPs, based on the use of zebrafish embryos as an intermediate screening step between cell culture assays and studies in rodents. MNPs with different cores, ferrite and manganese ferrite oxide, and sizes between 3 and 20 nm, were evaluated. Cell viability at a concentration of 50 μg/mL of PEGylated MNPs was above 90 % in all cases. However, the exposure of zebrafish embryos to manganese based MNPs at concentrations above 100 μg/mL showed a low survival rate (<50 %). In contrast, no mortality (survival rate ∼100 %) and normal hatching rate were obtained for the iron oxide MNPs. Based on these results, together with the physicochemical and magnetic properties (r 2  = 153.6 mM -1 ·s -1 ), the PEGylated 20 nm cubic shape iron oxide MNPs were selected and tested in mice, showing very good MRI contrast and, as expected, absence of toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

An interferon λ4 gene (IFNL4) knockout allele (rs368234815; TT) is associated with spontaneous and IFN-α-dependent cure of hepatitis C virus infection. The role of this polymorphism in the susceptibility to human immunodeficiency virus type 1 (HIV-1) infection is controversial. This study aimed to assess the association of this knockout IFNL4 variant and sexually transmitted HIV-1 infection. A total of 228 HIV-1-positive individuals and 136 HIV-exposed seronegative individuals were investigated for their association with IFNL4 rs368234815 genotypes. The IFNL4 ΔG functional allele is associated with increased susceptibility to HIV-1 infection through the sexual route (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6; P = .004). A meta-analysis including a population of injection drug users suggests a codominant mode of inheritance of this risk factor (OR, 2.0; 95% CI, 1.3-3.2; P = .001)., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Progress in the field of biocompatible SERS nanoparticles has promising prospects for biomedical applications. In this work, we have developed a biocompatible Raman probe by combining anisotropic silver nanoparticles with the dye rhodamine 6G followed by subsequent coating with bovine serum albumin. This nanosystem presents strong SERS capabilities in the near infrared (NIR) with a very high (2.7 × 10⁷) analytical enhancement factor. Theoretical calculations reveal the effects of the electromagnetic and chemical mechanisms in the observed SERS effect for this nanosystem. Finite element method (FEM) calculations showed a considerable near field enhancement in NIR. Using density functional quantum chemical calculations, the chemical enhancement mechanism of rhodamine 6G by interaction with the nanoparticles was probed, allowing us to calculate spectra that closely reproduce the experimental results. The nanosystem was tested in cell culture experiments, showing cell internalization and also proving to be completely biocompatible, as no cell death was observed. Using a NIR laser, SERS signals could be detected even from inside cells, proving the applicability of this nanosystem as a biocompatible SERS probe.

Objective: From an evolutionary perspective, emotions emerged as rapid adaptive reactions that increase survival rates. Current psychobiology includes the consideration that genetic changes affecting neuroendocrine and neurotransmission pathways may also be affecting mood states. Following this hypothesis, abnormal levels of any of the aminergic neurotransmitters would be of considerable importance in the development of a pathophysiological state., Materials and Methods: A total of 668 students from the School of Medicine of the University of Malaga (Average = 22.41 ± 3; 41% men) provided self-report measures of mood states using POMS and GHQ-28 questionnaires and buccal cells for genotyping 19 polymorphisms from 14 selected neurotransmitter pathways genes (HTR1A; HTR2A; HTR2C; HTR3B; TPH1; SLC18A1; SLC18A2; COMT; MAOA; MAOB) and neuroendocrine system (AVPR1B; OPRM1; BDNF; OXTR)., Results: MAOA rs3788862 genotype correlates with decreasing levels of Tension among females (beta = -0.168, p-value = 0.003) but it is neutral among males in this subscale. On the contrary, it correlates with lower GHQ-28 depression scores among males (beta = -0.196, p-value = 0.008). Equivalently, SLC18A1 and HTR2A variants correlated with anger and vigor scores, only among males. From the neuroendocrine system, OPRM1 rs1799971 correlated increasing levels of female's Anxiety, depression and Social Dysfunction scores., Conclusion: Our findings suggest that these polymorphisms contribute to define general population mood levels, although exhibiting a clear sexual dimorphism., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Introduction: Vitamin-D plays a role regulating the immune response against to viral infection. In this sense, vitamin-D deficiency may confer increased susceptibility to enveloped virus infection such as HIV, Hepatitis, Dengue and Respiratory Syncytial virus infection, among others. Vitamin D activity is mediated by its receptor (VDR), which acts as a transcription factor modulating the expression of genes triggering the response against viruses. To date, six major VDR polymorphisms (Cdx, A1012G, FokI, BsmI, ApaI and TaqI) have been studied in the context of viral infection susceptibility. Reported studies show controversial results probably due to statistical lack of power and population genetic differences., Aims: To do a systematic review of the published data and to perform a meta-analysis examining the role of six VDR polymorphisms on infection susceptibility to enveloped virus., Results: From all markers and virus considered an association of FokI polymorphism with RSV infection emerges as significant. The worldwide distribution of risk T-allele reveals a lower prevalence in African populations that runs parallel with the relative lower incidence of RSV-associated severe ALRI in children <1 year described in African samples., Conclusion: The results disclose FokI polymorphism as a relevant variant capturing the association of VDR polymorphisms with viral infection., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Oral anticoagulant treatments, such as vitamin K antagonists (VKAs), are the main treatments administered to atrial fibrillation (AF) patients in order to prevent ischemic stroke (IS). However, the genes involved in the VKA metabolism can undergo variations in a single nucleotide (SNP). These SNPs may then affect the VKA target enzyme (VKORC1), VKA degradation enzyme (CYP2C9), and vitamin K bioavailability enzyme (CYP4F2). We genotyped these SNPs in a cohort of patients with non-valvular AF who were under VKA treatment after suffering an IS. Clinical variables, CHADS2-VASC score and data about the international normalized ratio (INR) within the therapeutic range were all recorded. DNA was extracted from blood and genotyping was carried out by DNA sequencing. The main endpoint was the time from VKA onset to IS. Of a total of 356 consecutive IS patients monitored, 33 were included in the study. The median time to the event was 2248.0 days (interquartile range [IQR] 896.3-3545.3). The median CHADS2-VASC score was 4.0 (IQR 3.0-6.0). When we considered the risk of IS within 2 years under VKA treatment, we found that only the rs2108622 AA genotype was significantly associated with this endpoint (early IS) (hazard ratio 6.81, 95% CI 1.37-33.92, p = 0.019). Kaplan-Meier curve analysis also showed a significant relationship between early IS and rs2108622 AA genotype (Log rank p = 0.022). The CYP4F2 gene rs2108622 polymorphism was associated with a risk of early IS in NV-AF patients under VKA treatment.

Spermatozoa and neurones share similar membrane characteristics and features. Associations of multiple polymorphisms traditionally related to neurotransmission were investigated. Infertile men were grouped into controls with normospermia (n = 182) and idiopathic infertile men with asthenozoospermia (n = 103), and analysed as a case-control study and as a quantitative association of each genotype. Ten neurotransmission-associated genetic variants were mapped by SNP analysis using quantitative polymerase chain reaction with TaqMan probes. Men with HTR2A rs6313 had a higher risk of asthenozoospermia (OR = 2.14; P = 0.04). MAOA rs3788862 G carriers displayed an increased risk of asthenozoospermia (OR = 2.29; P = 0.02). The SLC18A1 rs1390938 G allele was more frequent among such cases (0.75 versus 0.87; P < 0.01 and P < 0.01 for Armitage trend test); for SLC18A1 rs2270641 P = 0.02 (case-control frequency) and P = 0.01 (Armitage trend test). MAOA rs3788862 was correlated with sperm motility (Spearman ρ = 0.14; P = 0.02); SLC18A1 rs1390938 was correlated with sperm count and motility (Spearman ρ = 0.20; P < 0.01). Gene polymorphisms of HTR2A, MAOA and SLC18A1, related to neurotransmission, are individually associated with asthenozoospermia through variation in sperm count and motility, without detectable allelic or genotype interaction., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Previous reports have proposed that personality may have played a role on human Out-Of-Africa migration, pinpointing some genetic variants that were positively selected in the migrating populations. In this work, we discuss the role of a common copy-number variant within the SIRPB1 gene, recently associated with impulsive behavior, in the human Out-Of-Africa migration. With the analysis of the variant distribution across forty-two different populations, we found that the SIRPB1 haplotype containing duplicated allele significantly correlated with human migratory distance, being one of the few examples of positively selected loci found across the human world colonization. Circular Chromosome Conformation Capture (4C-seq) experiments from the SIRPB1 promoter revealed important 3D modifications in the locus depending on the presence or absence of the duplication variant. In addition, a 3' enhancer showed neural activity in transgenic models, suggesting that the presence of the CNV may compromise the expression of SIRPB1 in the central nervous system, paving the way to construct a molecular explanation of the SIRPB1 variants role in human migration.

Studying host-pathogen interactions at a molecular level has been always technically challenging. Identifying the different biochemical and genetic pathways involved in the different stages of infection traditionally require complex molecular biology tools and often the use of costly animal models. In this chapter we illustrate a complementary approach to address host-pathogen interactions, taking advantage of the natural interindividual genetic diversity. The application of genetic association studies allows us to identify alleles involved in infection progression or resistance. Thus, this strategy may be useful to unravel new molecular pathways underlying host-pathogen interactions. Here we present the general steps that might be followed to plan, execute, and analyze a population-based study in order to identify genetic variants affecting human exposition to pathogens.

The mechanisms that can contribute in the fish movement strategies and the associated behaviour can be complex and related to the physiology, genetic and ecology of each species. In the case of the brown trout (Salmo trutta), in recent research works, individual differences in mobility have been observed in a population living in a high mountain river reach (Pyrenees, NE Spain). The population is mostly sedentary but a small percentage of individuals exhibit a mobile behavior, mainly upstream movements. Metabolomics can reflect changes in the physiological process and can determine different profiles depending on behaviour. Here, a non-targeted metabolomics approach was used to find possible changes in the blood metabolomic profile of S. trutta related to its movement behaviour, using a minimally invasive sampling. Results showed a differentiation in the metabolomic profiles of the trouts and different level concentrations of some metabolites (e.g. cortisol) according to the home range classification (pattern of movements: sedentary or mobile). The change in metabolomic profiles can generally occur during the upstream movement and probably reflects the changes in metabolite profile from the non-mobile season to mobile season. This study reveals the contribution of the metabolomic analyses to better understand the behaviour of organisms.

The present study was undertaken to determine the role of different polymorphisms affecting the testosterone/oestrogen pathway in miscarriage. Alpha 5-reductase (SRD5A2) rs523349 and rs9282858, cytochrome P450 aromatase (CYP19A1) rs4646, rs10046 and rs2236722 and oestrogen receptor (ESR1) rs9340799, rs2234693 and rs6932902 polymorphisms were selected. The case group consisted of 94 samples of formalin-fixed and paraffin-embedded fetal tissue from a miscarriage at ≤24 weeks. The control group comprised a population of 331 young healthy subjects. Only those single nucleotide polymorphisms (SNPs) fitting the Hardy-Weinberg equilibrium (n = 4) and euploid miscarriage samples (n = 67) were included for downstream analysis. Interestingly, SRD5A2 rs523349 (Val89Leu) was significantly associated with the risk of undergoing miscarriage after Bonferroni correction (odds ratio = 11.245, P < 2.2 × 10 -9 ). Moreover, when Mantel-Cox regression analysis was performed, we observed that the effect was significantly constrained to the second trimester (P = 0.024, log rank). These results are compatible with an imbalance of testosterone/dihydrotestosterone, associated with a higher risk of miscarriage, especially in late pregnancy., (Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Copy number variant (CNV) regions have been proven to have a significant impact on gene expression. Some of them have been also found to be associated to different human diseases. CNV genotyping is often prone to error and cross-validation with independent methods is frequently required. The platform of choice depends on whether it is a genome-wide discovery screening or a candidate CNV study, the cohort size and the number of CNVs included in the assay and, finally, the budget available. Here we illustrate a affordable approach to determine the CNV genotype using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and based on the quantitative determination of single nucleotide duplicated mismatches (SNDM) mapping the CNV region and a paralogue genomic region that is used as a two-copy reference. We have genotyped nsv436327, a common CNV mapping SIRPB1 intron 1 that has been associated to human personality behavior. SIRP cluster region was subjected to several ancestral duplication events what makes SIRPB1 CNV genotyping technically challenging. We designed three sets of primer pairs that amplified paralogue regions inside and outside the CNV, containing three SNDMs. Post-PCR extension analyses of sequencing oligonucleotides mapping immediately upstream each SNDM allowed us to quantify using MALDI-MS the proportion of PCR products derived from the CNV region versus the external reference. In contrast to other approaches, setting up this genotyping method requires an affordable investment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Impulsive-disinhibited personality (IDP) is a behavioral trait mainly characterized by seeking immediate gratification at the expense of more enduring or long-term gains. This trait has a major role in the development of several disinhibitory behaviors and syndromes, including psychopathy, attention-deficit and hyperactivity disorder, cluster-B personality disorders, criminality and alcoholism. Available data consistently support a strong heritable component, accounting for 30-60% of the observed variance in personality traits. A genome-wide analysis of copy-number variants was designed to identify novel genetic pathways associated with the IDP trait, using a series of 261 male participants with maximized opposite IDP scores. Quantitative trait locus analysis of candidate copy-number variants (CNVs) was conducted across the entire IDP continuum. Functional effects of associated variants were evaluated in zebrafish embryos. A common CNV mapping to the immune-related gene SIRPB1 was significantly associated with IDP scores in a dose-dependent manner (β=-0.172, P<0.017). Expression quantitative trait locus analysis of the critical region revealed higher SIRPB1 mRNA levels associated with the haplotype containing the deleted allele (P<0.0007). Epigenetic marks highlighted the presence of two potential insulators within the deleted region, confirmed by functional assays in zebrafish embryos, which suggests that SIRPB1 expression rates are affected by the presence/absence of the insulator regions. Upregulation of SIRPB1 has been described in prefrontal cortex of patients with schizophrenia, providing a link between SIRPB1 and diseases involving disinhibition and failure to control impulsivity. We propose SIRPB1 as a novel candidate gene to account for phenotypic differences observed in the IDP trait., (© 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Autism spectrum disorder (ASD) is a highly heritable disease (~0.9) with a complex genetic etiology. It is initially characterized by altered cognitive ability which commonly includes impaired language and communication skills as well as fundamental deficits in social interaction. Despite the large amount of studies described so far, the high clinical diversity affecting the autism phenotype remains poorly explained. Recent studies suggest that rare genomic variations, in particular copy number variation (CNV), may account for a significant proportion of the genetic basis of ASD. The use of disease-discordant monozygotic twins represents a powerful strategy to identify de novo and inherited CNV in the disorder. Here we present the results of a comparative genome hybridization (CGH) analysis with a pair of monozygotic twins affected of ASD with significant differences in their clinical manifestations that specially affect speech language impairment and communication skills. Array CGH was performed in three different tissues: blood, saliva, and hair follicle, in an attempt to identify germinal and somatic CNV regions that may explain these differences. Our results argue against a role of large CNV rearrangements as a molecular etiology of the observed differences. This forwards future research to explore de novo point mutation and epigenomic alterations as potential explanations of the observed clinical differences.