scholarly journals Hematopoietic mosaic chromosomal alterations in the New England Centenarian Study

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 679-680
Author(s):  
Anastasia Leshchyk ◽  
Giulio Genovese ◽  
Stefano Monti ◽  
Thomas Perls ◽  
Paola Sebastiani
Keyword(s):  
New England ◽  
Neutral Loss ◽  
Large Population ◽  
Population Based ◽  
Steady Increase ◽  
Base Pairs ◽  
Chromosomal Alterations ◽  
Dna Microarray Data ◽  
R Ratio ◽  
Genome Wide

Abstract Mosaic chromosomal alterations (mCAs) are structural alterations that include deletions, duplications, or copy-neutral loss of heterozygosity. mCAs are reported to be associated with survival, age, cancer, and cardiovascular disease. Previous studies of mCAs in large population-based cohorts (UK Biobank, MGBB, BioBank Japan, and FinnGen) have demonstrated a steady increase of mCAs as people age. The distribution of mCAs in centenarians and their offspring is not well characterized. We applied MOsaic CHromosomal Alteration (MoChA) caller on 2298 genome-wide genotype samples of 1582 centenarians, 443 centenarians’ offspring, and 273 unrelated controls from the New England Centenarian Study (NECS). Integrating Log R ratio and B-allele frequency (BAF) intensities with genotype phase information, MoChA employs a Hidden Markov Model to detect mCA-induced deviations in allelic balance at heterozygous sites consistent with genotype phase in the DNA microarray data. We analyzed mCAs spanning over 100 k base pairs, with an estimated cell fraction less than 50%, within samples with genome-wide BAF phase concordance across phased heterozygous sites less than 0.51, and with LOD score of more than 10 for the model based on BAF and genotype phase. Our analysis showed that somatic mCAs increase with older age up to approximately 102 years, but the prevalence of the subjects with mCAs tend to decrease after that age, thus suggesting that accumulation of mCAs is less prevalent in long-lived individuals. We also used Poisson regression to show that centenarians and their offspring tend to accumulate less mCA (RR = 0.63, p=0.045) compared to the controls.

scholarly journals CLONAL HEMATOPOIESIS IN A CENTENARIAN COHORT

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S105-S106
Author(s):  
Aparna Bhutkar ◽  
Anastasia Gurinovich ◽  
Thomas T Perls ◽  
Paola Sebastiani ◽  
Stefano Monti
Keyword(s):  
New England ◽  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Neutral Loss ◽  
Single Individual ◽  
Copy Number State ◽  
Chromosomal Alterations ◽  
R Ratio ◽  
Chromosomal Alteration ◽  
Extreme Longevity

Abstract Mosaicism, the presence of two or more genotypically or karyotypically distinct populations of cells in a single individual, plays an important role in human disease. Mosaicism can result in mutations and/or chromosomal alterations such as loss, gain, or copy-number neutral loss of heterozygosity. Clonal mosaicism and its relationship to aging and cancer, has been previously studied, and earlier work suggests that clonal mosaicism tends to increase with age. The aim of our research is to use genotype data of centenarians to explore the relationship between extreme longevity and mosaic chromosomal alterations (mCAs). To this end, we analyzed genome-wide genotypes from blood-derived DNA of 338 individuals from the New England Centenarian Study. The participants in this dataset ranged from 45 to 112 years of age. For the detection of mCA events, we used MoChA (https://github.com/freeseek/mocha), a bcftools extension, that predicts mCAs based on B-allele frequency (BAF) and log2 intensity(R) ratio (LRR), and uses long-range phase information to increase sensitivity. Chromosomal alteration events, including whole chromosome events, were detected in 180 out of the 338 individuals. A total of 165 duplications, 97 deletions, and 9 copy-number neutral loss of heterozygosity were detected. Additionally, there were 42 events whose copy number state could not be determined with high confidence. 236 events out of the 313 were detected in individuals aged 100 and older. Our analysis of chromosomal alteration frequency by age indicates that, within centenarians, the proportion of individuals with mCAs significantly decreases with increased age (p < 0.05, correlation -0.73).

scholarly journals 85. GENOME-WIDE-ASSOCIATION AND POLYGENIC ARCHITECTURE OF SINGLE AND RECURRENT DEPRESSION EPISODES IN A LARGE POPULATION-BASED SAMPLE

2021 ◽  
Vol 51 ◽  
pp. e85-e86
Author(s):  
Thomas Als ◽  
Jakob Grove ◽  
Janne Thirstrup ◽  
Veera Rajagopal ◽  
Jonas Bybjerg-Grauholm ◽  
...  
Keyword(s):  
Large Population ◽  
Population Based ◽  
Genome Wide Association ◽  
Recurrent Depression ◽  
Genome Wide

Antiphospholipid antibodies in a large population-based cohort: genome-wide associations and effects on monocyte gene expression

2016 ◽  
Vol 116 (07) ◽  
pp. 115-123 ◽  
Author(s):  
Nadine Müller-Calleja ◽  
Heidi Rossmann ◽  
Christian Müller ◽  
Philipp Wild ◽  
Stefan Blankenberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antiphospholipid Antibodies ◽  
Ex Vivo ◽  
Genetic Locus ◽  
Large Population ◽  
Population Based ◽  
Chromosome 17 ◽  
Health Study ◽  
Genome Wide

SummaryThe antiphospholipid syndrome (APS) is characterised by venous and/ or arterial thrombosis and pregnancy morbidity in women combined with the persistent presence of antiphospholipid antibodies (aPL). We aimed to identify genetic factors associated with the presence of aPL in a population based cohort. Furthermore, we wanted to clarify if the presence of aPL affects gene expression in circulating monocytes. Titres of IgG and IgM against cardiolipin, D2glycoprotein 1 (antiD2GPI), and IgG against domain 1 of D2GPI (anti-domain 1) were determined in approx. 5,000 individuals from the Gutenberg Health Study (GHS) a population based cohort of German descent. Genotyping was conducted on Affymetrix Genome-Wide Human SNP 6.0 arrays. Monocyte gene expression was determined in a subgroup of 1,279 individuals by using the Illumina HT-12 v3 BeadChip. Gene expression data were confirmed in vitro and ex vivo by qRT-PCR. Genome wide analysis revealed significant associations of anti-D2GPI IgG and APOH on chromosome 17, which had been previously identified by candidate gene approaches, and of anti-domain1 and MACROD2 on chromosome 20 which has been listed in a previous GWAS as a suggestive locus associated with the occurrence of anti-D2GPI antibodies. Expression analysis confirmed increased expression of TNFD in monocytes and identified and confirmed neuron navigator 3 (NAV3) as a novel gene induced by aPL. In conclusion, MACROD2 represents a novel genetic locus associated with aPL. Furthermore, we show that aPL induce the expression of NAV3 in monocytes and endothelial cells. This will stimulate further research into the role of these genes in the APS.

scholarly journals Pan cancer patterns of allelic imbalance from chromosomal alterations in 33 tumor types

Genetics ◽  
2021 ◽  
Vol 217 (1) ◽  
Author(s):  
Smruthy Sivakumar ◽  
F Anthony San Lucas ◽  
Yasminka A Jakubek ◽  
Zuhal Ozcan ◽  
Jerry Fowler ◽  
...  
Keyword(s):  
Copy Number ◽  
Recurrent Events ◽  
Allelic Imbalance ◽  
Neutral Loss ◽  
Allele Frequencies ◽  
The Cancer Genome Atlas ◽  
Chromosomal Alterations ◽  
R Ratio ◽  
Binary Segmentation ◽  
Pan Cancer

Abstract Somatic copy number alterations (SCNAs) serve as hallmarks of tumorigenesis and often result in deviations from one-to-one allelic ratios at heterozygous loci, leading to allelic imbalance (AI). The Cancer Genome Atlas (TCGA) reports SCNAs identified using a circular binary segmentation algorithm, providing segment mean copy number estimates from single-nucleotide polymorphism DNA microarray total intensities (log R ratio), but not allele-specific intensities (“B allele” frequencies) that inform of AI. Our approach provides more sensitive identification of SCNAs by modeling the “B allele” frequencies jointly, thereby bolstering the catalog of chromosomal alterations in this widely utilized resource. Here we present AI summaries for all 33 tumor sites in TCGA, including those induced by SCNAs and copy-neutral loss-of-heterozygosity (cnLOH). We identified AI in 94% of the tumors, higher than in previous reports. Recurrent events included deletions of 17p, 9q, 3p, amplifications of 8q, 1q, 7p, as well as mixed event types on 8p and 13q. We also observed both site-specific and pan-cancer (spanning 17p) cnLOH, patterns which have not been comprehensively characterized. The identification of such cnLOH events elucidates tumor suppressors and multi-hit pathways to carcinogenesis. We also contrast the landscapes inferred from AI- and total intensity-derived SCNAs and propose an automated procedure to improve and adjust SCNAs in TCGA for cases where high levels of aneuploidy obscured baseline intensity identification. Our findings support the exploration of additional methods for robust automated inference procedures and to aid empirical discoveries across TCGA.

scholarly journals MARS: a tool for haplotype-resolved population-based structural variation detection

2021 ◽  
Author(s):  
Lu Zhang ◽  
Arend Sidow ◽  
Xin Zhou
Keyword(s):  
Structural Variation ◽  
Large Population ◽  
High Sensitivity ◽  
Population Based ◽  
Multiple Alignment ◽  
Structural Variants ◽  
Validation Rate ◽  
Global View ◽  
Genome Wide ◽  
Genome Assemblies

Motivation: Linked-reads enables genome-wide phased diploid assemblies. These haplotype-resolved assemblies allow us to genotype structural variants (SVs) with a high sensitivity and be able to further phase them. Yet, existing SV callers are designed for haploid genome assemblies only, and there is no tool to call SV from a large population of diploid assemblies which can define and refine SVs from a global view. Results: We introduce MARS (Multiple Alignment-based Refinement of Svs) in linked-reads for the detection of the most common SV types - indels from diploid genome assemblies of a large population. We evaluated SVs from MARS based on Mendelian law of inheritance and PacBio HiFi reads and it achieved a high validation rate around 73%-87% for indels that we have selected from 34 assembled samples.

Suicide and Psychosis: Results From a Population-Based Cohort of Suicide Death (N = 4380)

2021 ◽  
Author(s):  
Anna R Docherty ◽  
Amanda V Bakian ◽  
Emily DiBlasi ◽  
Andrey A Shabalin ◽  
Danli Chen ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Large Population ◽  
Population Based ◽  
Suicide Death ◽  
Genetics Research ◽  
Affective Symptoms ◽  
Genome Wide ◽  
Increased Risk ◽  
Genetic Risks ◽  
Genome Wide Data

Abstract Approximately 5% of individuals with schizophrenia die from suicide. However, suicide in psychosis is still poorly characterized, partly due to a lack of adequate population-based clinical or genetic data on suicide death. The Utah Suicide Genetics Research Study (USGRS) provides a large population-based cohort of suicide deaths with medical record and genome-wide data (N = 4380). Examination of this cohort identified medical and genetic risks associated with type of suicide death and investigated the relative contributions of psychotic and affective symptoms to method of suicide. Key differences in method of suicide (common vs. atypical methods) were tested in relation to lifetime psychosis and genome-wide genetic risk for schizophrenia, major depressive disorder, and neuroticism. Consistent with previous studies, psychosis-spectrum disorders were observed to be common in suicide (15% of the cohort). Individuals with psychosis more frequently died from atypical methods, with rates of atypical suicide increasing across the schizophrenia spectrum. Genetic risk for schizophrenia was also associated with atypical suicide, regardless of clinical diagnosis, though this association weakened when filtering individuals with schizophrenia from the analysis. Follow-up examination indicated that high rates of atypical suicide observed in schizophrenia are not likely accounted for by restricted access to firearms. Overall, better accounting for the increased risk of atypical suicide methods in psychosis could lead to improved prevention strategies in a large portion of the suicide risk population.

scholarly journals Phenotypic and genetic markers of psychopathology in a population-based sample of older adults

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Arianna M. Gard ◽  
Erin B. Ware ◽  
Luke W. Hyde ◽  
Lauren L. Schmitz ◽  
Jessica Faul ◽  
...  
Keyword(s):  
Older Adults ◽  
Large Population ◽  
The United States ◽  
Population Based ◽  
European Ancestry ◽  
Equation Modeling ◽  
General Factor ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Polygenic Scores

AbstractAlthough psychiatric phenotypes are hypothesized to organize into a two-factor internalizing–externalizing structure, few studies have evaluated the structure of psychopathology in older adults, nor explored whether genome-wide polygenic scores (PGSs) are associated with psychopathology in a domain-specific manner. We used data from 6003 individuals of European ancestry from the Health and Retirement Study, a large population-based sample of older adults in the United States. Confirmatory factor analyses were applied to validated measures of psychopathology and PGSs were derived from well-powered genome-wide association studies (GWAS). Genomic SEM was implemented to construct latent PGSs for internalizing, externalizing, and general psychopathology. Phenotypically, the data were best characterized by a single general factor of psychopathology, a factor structure that was replicated across genders and age groups. Although externalizing PGSs (cannabis use, antisocial behavior, alcohol dependence, attention deficit hyperactivity disorder) were not associated with any phenotypes, PGSs for major depressive disorder, neuroticism, and anxiety disorders were associated with both internalizing and externalizing phenotypes. Moreover, the variance explained in the general factor of psychopathology increased by twofold (from 1% to 2%) using the latent internalizing or latent one-factor PGSs, derived using weights from Genomic Structural Equation Modeling (SEM), compared with any of the individual PGSs. Collectively, results suggest that genetic risk factors for and phenotypic markers of psychiatric disorders are transdiagnostic in older adults of European ancestry. Alternative explanations are discussed, including methodological limitations of GWAS and phenotypic measurement of psychiatric outcome in large-scale population-based studies.

scholarly journals The molecular genetics of hand preference revisited

2018 ◽  
Author(s):  
Carolien G.F. de Kovel ◽  
Clyde Francks
Keyword(s):  
Complex Traits ◽  
Large Population ◽  
Enrichment Analysis ◽  
Hand Preference ◽  
Population Based ◽  
Gene Set Enrichment Analysis ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

AbstractHand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N=331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence implicating any specific candidate variants previously reported. We also found no evidence that genes involved in visceral laterality play a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Within the UK Biobank itself, a significant association implicates the gene MAP2 in handedness.

scholarly journals A Genome-Wide Linkage Scan for Age at Menarche in Three Populations of European Descent

2008 ◽  
Vol 93 (10) ◽  
pp. 3965-3970 ◽  
Author(s):  
Carl A. Anderson ◽  
Gu Zhu ◽  
Mario Falchi ◽  
Stéphanie M. van den Berg ◽  
Susan A. Treloar ◽  
...  
Keyword(s):  
Pubertal Development ◽  
Large Population ◽  
Population Based ◽  
Chromosome 12 ◽  
Age At Menarche ◽  
Genome Wide ◽  
Three Samples ◽  
A Genome ◽  
Trait Locus ◽  
Clinically Significant

Context: Age at menarche (AAM) is an important trait both biologically and socially, a clearly defined event in female pubertal development, and has been associated with many clinically significant phenotypes. Objective: The objective of the study was to identify genetic loci influencing variation in AAM in large population-based samples from three countries. Design/Participants: Recalled AAM data were collected from 13,697 individuals and 4,899 pseudoindependent sister-pairs from three different populations (Australia, The Netherlands, and the United Kingdom) by mailed questionnaire or interview. Genome-wide variance components linkage analysis was implemented on each sample individually and in combination. Results: The mean, sd, and heritability of AAM across the three samples was 13.1 yr, 1.5 yr, and 0.69, respectively. No loci were detected that reached genome-wide significance in the combined analysis, but a suggestive locus was detected on chromosome 12 (logarithm of the odds = 2.0). Three loci of suggestive significance were seen in the U.K. sample on chromosomes 1, 4, and 18 (logarithm of the odds = 2.4, 2.2 and 3.2, respectively). Conclusions: There was no evidence for common highly penetrant variants influencing AAM. Linkage and association suggest that one trait locus for AAM is located on chromosome 12, but further studies are required to replicate these results.

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