An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 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. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß 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 SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.

A Genome-Wide Association Study of Small Cell Lung Cancer

Introduction: Small cell lung cancer (SCLC) comprises 10–15% of all lung cancer cases and is the most aggressive histological type. Survival is poor and the molecular landscape of this disease is extraordinarily complex. The objective of this paper was to perform a Genome-Wide Association Study (GWAS) of this disease using a case–control study specifically designed for small cell lung cancer (SCLC). Methods: Incident cases were consecutively recruited from 8 hospitals from different regions of Spain. Controls were recruited from the same hospitals using a frequency sampling based on age and sex distribution of cases. Biological samples were obtained along with detailed information on cases and controls lifestyle, including tobacco and radon exposure. Results: We included 271 SCLC cases and 557 controls. We found evidence (p-values<10−5) of an association in the complete dataset for several loci, while MAP4 showed a significant association in the gene-based analysis. Pathway analysis suggested that ATR, ATRIP, MCM4, MCM5, ORC4, RPA3 and CDC25A genes have a role on the onset of SCLC. Conclusion: This study provides biological evidence for pathways related to SCLC, offering novel loci for further research. (AU)

A Genome-Wide Association Study of Small Cell Lung Cancer.

INTRODUCTION: Small cell lung cancer (SCLC) comprises 10-15% of all lung cancer cases and is the most aggressive histological type. Survival is poor and the molecular landscape of this disease is extraordinarily complex. The objective of this paper was to perform a Genome-Wide Association Study (GWAS) of this disease using a case-control study specifically designed for small cell lung cancer (SCLC). METHODS: Incident cases were consecutively recruited from 8 hospitals from different regions of Spain. Controls were recruited from the same hospitals using a frequency sampling based on age and sex distribution of cases. Biological samples were obtained along with detailed information on cases and controls lifestyle, including tobacco and radon exposure. RESULTS: We included 271 SCLC cases and 557 controls. We found evidence (p-values<10-5) of an association in the complete dataset for several loci, while MAP4 showed a significant association in the gene-based analysis. Pathway analysis suggested that ATR, ATRIP, MCM4, MCM5, ORC4, RPA3 and CDC25A genes have a role on the onset of SCLC. CONCLUSION: This study provides biological evidence for pathways related to SCLC, offering novel loci for further research.

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer's Disease Aetiopathogenesis in Men.

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.

Multi-omics signatures of the human early life exposome.

Environmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1301 mother-child pairs, we associate individual exposomes consisting of >100 chemical, outdoor, social and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, proteins and metabolites) in childhood. We identify 1170 associations, 249 in pregnancy and 921 in childhood, which reveal potential biological responses and sources of exposure. Pregnancy exposures, including maternal smoking, cadmium and molybdenum, are predominantly associated with child DNA methylation changes. In contrast, childhood exposures are associated with features across all omics layers, most frequently the serum metabolome, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions, among others. Our comprehensive and unique resource of all associations ( https://helixomics.isglobal.org/ ) will serve to guide future investigation into the biological imprints of the early life exposome.

Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children's blood.

Background: The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children's blood, using data from 832 children of the Human Early Life Exposome (HELIX) project. Methods: Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition. Results: We identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGene's TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. In 40.4% of the eQTMs, the CpG and the eGene were both associated with at least one genetic variant. The overlap of autosomal cis eQTMs in children's blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants. Conclusions: This catalogue of autosomal cis eQTMs in children's blood can help the biological interpretation of EWAS findings and is publicly available at https://helixomics.isglobal.org/ and at Dryad (doi:10.5061/dryad.fxpnvx0t0). Funding: The study has received funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project); the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project); from the European Union's Horizon 2020 research and innovation programme under grant agreement no 733206 (LIFECYCLE project), and from the European Joint Programming Initiative "A Healthy Diet for a Healthy Life" (JPI HDHL and Instituto de Salud Carlos III) under the grant agreement no AC18/00006 (NutriPROGRAM project). The genotyping was supported by the projects PI17/01225 and PI17/01935, funded by the Instituto de Salud Carlos III and co-funded by European Union (ERDF, "A way to make Europe") and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; "Rhea Plus": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). We acknowledge support from the Spanish Ministry of Science and Innovation through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. MV-U and CR-A were supported by a FI fellowship from the Catalan Government (FI-DGR 2015 and #016FI_B 00272). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (CD12/00563 and MS16/00128).

Cells can fine-tune which genes they activate, when and at which levels using a range of chemical marks on the DNA and certain proteins that help to organise the genome. One well-known example of such 'epigenetic tags' is DNA methylation, whereby a methyl group is added onto particular positions in the genome. Many factors ­ including environmental effects such as diet ­ control DNA methylation, allowing an organism to adapt to ever-changing conditions. An expression quantitative trait methylation (eQTM) is a specific position of the genome whose DNA methylation status regulates the activity of a given gene. A catalogue of eQTMs would be useful in helping to reveal how the environment and disease impacts the way cells work. Yet, currently, the relationships between most epigenetic tags and gene activity remains unclear, especially in children. To fill this gap, Ruiz-Arenas et al. studied DNA methylation in blood samples from over 800 healthy children across Europe. Amongst all tested DNA methylation sites, 22,000 (5.7% of total) were associated with the expression of a gene ­ and therefore were eQTMs; reciprocally, 9,000 genes (15.3% of all tested genes) were linked to at least one methylation site, leading to a total of 40,000 pairs of DNA methylation sites and genes. Most often, eQTMs regulated the expression of nearby genes ­ but only half controlled the gene that was the closest to them. Age and the genetic background of the individuals influenced the nature of eQTMs. This catalogue is a useful resource for the scientific community to start understanding the relationship between epigenetics and gene activity. Similar studies are now needed for other tissues and age ranges. Overall, extending our knowledge of eQTMs may help reveal how life events lead to illness, and could inform prevention efforts.

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study.

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.

Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study.

Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the "Axiom Spanish Biobank" array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10-5, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10-5, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10-5, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10-5, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10-5, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10-2, p = 5.1 × 10-3, p = 1.2 × 10-2, respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory response.

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

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.

Genome-wide association study of stage III/IV grade C periodontitis (former aggressive periodontitis) in a Spanish population.

AIM: To identify loci associated with stages III/IV, grade C periodontitis (PIII/IV-C) through a genome-wide association study (GWAS). MATERIALS AND METHODS: 441 Caucasian Spanish PIII/IV-C cases from the SEPA Network of Research Clinics and 1141 controls from the Banco Nacional de ADN were genotyped with "Axiom Spain Biobank Array," which contains 757836 markers, including rare and low-frequency Spanish variants. The analysis of the individual association and subsequently the gene-level analysis with Sequence Kernel Association Test (SKAT) were carried out adjusting for age, sex and PC1 covariates. Pathway Analysis was additionally performed with Ingenuity Pathway Analysis (IPA) software on the top associated genes. RESULTS: In the individual analyses, no genome-wide significant signals were detected. However, 8 SNPs of 8 loci reached suggestive evidence of association with PIII/IV-C, including FAT3 rs35709256, CSNK1G2 rs4807188, MYH13 rs2074872, CNTN2 rs116611488, ANTXR1 rs4854545, 8p23.2 rs78672540, ANGPT1 rs13439823 and PLEC rs11993287 (p < 5 × 10-6 ). SKAT analysis identified other interesting signals at CNTN2, FBXO44, AP1M2, RSPO4, KRI1, BPIFB1 and INMT, although their probability does not exceed the multiple-test correction. IPA indicated significant enrichment of pathways related to cAMP, IL-2, CD28, VDR/RXR and PI3K/Akt.  CONCLUSIONS: GWAS found no SNPs significantly associated with PIII/IV-C.

Long runs of homozygosity are associated with 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 [ßAVROH (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10-5; ßFROH (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), (ß (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.

Differential admixture in Latin American populations and its impact on the study of colorectal cancer.

Genome-wide association studies focused on searching genes responsible for several diseases. Admixture mapping studies proposed a more efficient alternative capable of detecting polymorphisms contributing with a small effect on the disease risk. This method focuses on the higher values of linkage disequilibrium in admixed populations. To test this, we analyzed 10 genomic regions previously defined as related with colorectal cancer among nine populations and studied the variation pattern of haplotypic structures and heterozygosity values on seven categories of SNPs. Both analyses showed differences among chromosomal regions and studied populations. Admixed Latin-American samples generally show intermediate values. Heterozygosity of the SNPs grouped in categories varies more in each gene than in each population. African related populations have more blocks per chromosomal region, coherently with their antiquity. In sum, some similarities were found among Latin American populations, but each chromosomal region showed a particular behavior, despite the fact that the study refers to genes and regions related with one particular complex disease. This study strongly suggests the necessity of developing statistical methods to deal with di- or tri-hybrid populations, as well as to carefully analyze the different historic and demographic scenarios, and the different characteristics of particular chromosomal regions and evolutionary forces.

In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children.

BACKGROUND: The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows. METHODS: We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites. RESULTS: Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure. CONCLUSION: In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis.

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.

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.

Patterns of genetic differentiation and the footprints of historical migrations in the Iberian Peninsula.

The Iberian Peninsula is linguistically diverse and has a complex demographic history, including a centuries-long period of Muslim rule. Here, we study the fine-scale genetic structure of its population, and the genetic impacts of historical events, leveraging powerful, haplotype-based statistical methods to analyse 1413 individuals from across Spain. We detect extensive fine-scale population structure at extremely fine scales (below 10 Km) in some regions, including Galicia. We identify a major east-west axis of genetic differentiation, and evidence of historical north to south population movement. We find regionally varying fractions of north-west African ancestry (0-11%) in modern-day Iberians, related to an admixture event involving European-like and north-west African-like source populations. We date this event to 860-1120 CE, implying greater genetic impacts in the early half of Muslim rule in Iberia. Together, our results indicate clear genetic impacts of population movements associated with both the Muslim conquest and the subsequent Reconquista.

The effect of copy number variations in chromosome 16p on body weight in patients with intellectual disability.

Syndromic monogenic obesity is a rare and severe early-onset form of obesity. It is characterized by intellectual disability, congenital malformations, and/or dysmorphic facies. The diagnosis of patients is challenging due to the genetic heterogenicity of this condition. However, the use of microarray technology in combination with public databases has been successful on genotype-phenotype correlations, especially for body mass index (BMI) alteration. In this study, the relationship between copy number variations (CNVs) detected by microarray mapping on 16p region and BMI alterations in syndromic patients were assessed. In order to achieve this goal, 680 unrelated Spanish children with intellectual disability were included. 16p region was characterized by using microarray platforms. All detected variants were classified as: (I) one previously non-described 10-Mb duplication in 16p13.2p12.3 region considered causal of intellectual disability and severe overweight, and (II) eleven 16p11.2 CNVs of low prevalence but with recurrence in syndromic patients with severe BMI alteration (nine proximal and two distal). Proximal 16p11.2 CNVs have a dose-dependent effect: underweight in carriers of duplication and obesity in carriers of deletion. KCTD13 was identified as a possible candidate gene for BMI alteration on proximal syndromes, whereas SH2B1 gene was identified as candidate for distal syndromes. The results shown in this paper suggest that syndromic patients could constitute a reliable model to evaluate hypothalamic satiety and obesity disorders as well as generate a wide expectation for primary prevention of comorbidities. Furthermore, 16p13.2p12.3 showed to be an important region on the regulation of body fatness.

Assessment of genotyping tools applied in genetic susceptibility studies of periodontal disease: A systematic review.

OBJECTIVE: A systematic review to evaluate the various genotyping tools and study strategies employed to define genetic susceptibility to periodontitis. METHODS: The review was performed in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. The search for publications referring to the genetic bases of periodontal disease was performed on the MEDLINE-PubMed and Cochrane Library databases, on trials registers, and on the web pages of regulatory agencies. RESULTS: We found 2439 potentially eligible articles, of which only 25 satisfied the established inclusion criteria and were processed for data extraction. The review revealed marked heterogeneity between studies, caused in part by the lack of a universally accepted definition for periodontitis phenotypes and by the variety of genotyping tools available. The most commonly used technique was genotyping candidate genes. CONCLUSION: The few rigorous studies that have been published on genetic susceptibility to periodontitis are subject to severe methodological bias due to their design and the genotyping tools employed. Despite their limitations, candidate gene studies continue to be the predominant methodological approach, rather than genome-wide association studies. Further studies must be designed using a universally accepted, validated diagnostic criterion for periodontitis, analysing multiple genes and polymorphisms in combination with rare variants.