Biology subjects

de Rojas, I.

Publications and source records attributed to de Rojas, I..

4 recordsLinked to original sources

bioRxiv2022

What does heritability of Alzheimer's disease represent?

INTRODUCTIONBoth Alzheimers disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. METHODSWe compute heritability in five large independent cohorts (N=7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set. RESULTSSNP-based heritability of Alzheimers disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD=8%] on average when the APOE region is excluded and an additional 1% [SD=3%] when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts. CONCLUSIONThe heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes. Author SummaryEstimates of heritability in Alzheimers disease, the proportion of phenotypic variance explained by genetics, are very varied across different studies, therefore, the amount of missing heritability not yet captured by current genome-wide association studies is debated. We investigate this in five independent cohorts, provide estimates based on these cohorts and detail necessary suggestions to accurately calculate heritability in age-related disorders. We also confirm the importance of microglia relevant genetic markers in Alzheimers disease. This manuscript provides suggestions for other researchers computing heritability in late-onset disorders and the microglia gene-set used in this study will be published alongside this manuscript and made available to other researchers. The correct assessment of disease heritability will aid in better understanding the amount of missing heritability in Alzheimers disease.

genetics↗

bioRxiv2020

Autosomal Recessive Alzheimer disease (arAD): homozygosity mapping of genomic regions containing arAD loci

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of recent inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimers disease (AD). However, the search for recessive variants has been poorly assessed to date. To investigate homozygosity in AD, we performed a fine-scale ROH analysis including 21,100 individuals from 10 cohorts of European ancestry (11,919 AD cases and 9,181 controls). We detected an increase of homozygosity in AD cases compared to controls [{beta}FROH (CI95%) = 0.051 (0.023 - 0.078); P = 3.25 x 10-4]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 x 10-16). The top associated ROH with AD risk ({beta} (CI95%) = 1.09 (0.48 - 1.48), p value = 9.03 x 10-4) was detected upstream the HS3ST1 locus (chr4:11,189,482-11,305,456), previously related to AD. Next, to construct a homozygosity map of AD cases, we selected ROHs shared by inbred AD cases extracted from an outbred population. We used whole-exome sequencing data from 1,449 individuals from the Knight-ADRC-NIA-LOAD (KANL) cohort to identify potential recessive variants in candidate ROHs. 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.

genetics↗

bioRxiv2019

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

BackgroundGenetics plays a major role in Alzheimers Disease (AD). To date, 40 genes associated with AD have been identified, although most remain undiscovered. Clinical, neuropathological and genetic variability might impact genetic discoveries and complicate dissection of the biological pathways underlying AD. MethodsGR@ACE is a genome-wide study of dementia and its clinical endophenotypes that encompasses 4,120 cases and 3,289 controls from Spain. GR@ACE phenotypes were defined according to ADs clinical certainty and the presence of vascular co-morbidity. To explore whether clinical endophenotypes reflect variation in underlying biological pathways, we first assessed the impact of known AD loci across endophenotypes to generate three loci categories. Next, we incorporated gene co-expression data and conducted pathway analysis on each category. To assess the impact of heterogeneity in the GWAS findings, the GR@ACE series were meta-analyzed with: 1) genotype-level data from dbGaP (N=21,235); and 2) summary statistics from IGAP Stages I and II (n=61,571 and n=81,455 respectively). FindingsWe classified known AD loci in three categories, which might reflect the disease clinical heterogeneity, from vascular and mixed forms to pure AD pathology. Immune system pathways were detected in all categories. Intriguingly, vascular processes were only detected as a causal mechanism in probable AD. A meta-analysis of GR@ACE with additional GWAS datasets revealed the ANKRD31-rs4704171 signal in the HMGCR genomic region. We confirmed NDUFAF6-rs10098778 and SCIMP-rs7225151, which were previously detected by IGAP, to be suggestive signals. We also confirmed CD33-rs3865444 to be genome-wide significant. InterpretationThe regulation of vasculature is a prominent causal component of probable AD. In that context, cerebral amyloid angiopathy, the unique identified link between the vascular and amyloid hypotheses, deserves further investigation. The GR@ACE meta-analysis revealed novel AD genetic signals. GWAS results are strongly driven by the presence of clinical heterogeneity in the AD series. FundingGrifols SA, Fundacion bancaria "La Caixa", Fundacio ACE and ISCIII (Instituto de Salud Carlos III).

neuroscience↗

bioRxiv2018

Genome Wide Meta-Analysis identifies new loci associated with cardiac phenotypes and uncovers a common genetic signature shared by heart function and Alzheimer’s disease

AimsEchocardiography has become an indispensable tool for the study of heart performance, improving the monitoring of individuals with cardiac diseases. Diverse genetic factors associated with echocardiographic measures of heart structure and functions have been previously reported. The impact of several apoptotic genes in heart development identified in experimental models prompted us to assess their potential association with indicators of human cardiac function. This study started with the aim to investigate the possible association of variants of apoptotic genes with echocardiographic traits and to identify new genetic markers associated with cardiac function.\n\nMethods and resultsGenome wide data from different studies were obtained from public repositories. After quality control and imputation, association analyses confirm the role of caspases and other apoptosis related genes with cardiac phenotypes. Moreover, enrichment analysis showed an over-representation of genes, including some apoptotic regulators, associated with Alzheimers disease (AD). We further explored this unexpected observation which was confirmed by genetic correlation analyses.\n\nConclusionsOur findings show the association of apoptotic gene variants with echocardiographic indicators of heart function and reveal a novel potential genetic link between echocardiographic measures in healthy populations and cognitive decline later on in life. These findings may have important implications for preventative strategies combating Alzheimers disease.

genetics↗