He continues to pursue development of novel methodology to better analyse and understand the role of genetic variation in social and behavioral traits. Isabella Wilson ... With one simple test, you can discover your genetic origins and find family you never knew you had. While working with the deCODE data, Alex developed a novel method for estimating heritability using genetic data on parents and offspring. This implies that any genetic variant that is differentiated between these subpopulations (which is usually due to chance, i.e. 2020 Jun 1;3(6):e2012270. Myelin is the fatty covering that insulates nerve fibers and promotes the rapid transmission of nerve impulses. Preprint. Alexander I. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). Pairs of individuals who share a recent common ancestor are more likely to have similar environments than those who do not, implying that the GREML methodology could mistakenly infer contributions from rare genetic variants that are in fact environmental contributions. It is one of a group of disorders, called leukodystrophies, that involve the destruction of myelin. No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, https://doi.org/10.1371/journal.pgen.1008222, https://www.youtube.com/watch?v=B7ub92OLw1g. The first challenge is one of precision. We can examine existing heritability estimates from RDR and Sib-Regression (Table 1) to get a sense of what we might expect from precise GREML-WGS estimates. Alexander has 2 jobs listed on their profile. Yes The final date of follow-up was May 16, 2020. The estimates are taken from Young et al. 2020 Jul;19(7):102568. doi: 10.1016/j.autrev.2020.102568. 7.9%) when combined with a previous estimate [30].
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Author information: (1)Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. The GREML-WGS methodology measures the contribution from rare variants in part by measuring the degree to which pairs of individuals who share rare variants tend to have more similar phenotypes than people who do not. Please enable it to take advantage of the complete set of features! alexander.young@bdi.ox.ac.uk. Teaching assistant for Simon Myers course for masters level mathematicians: Stochastic Models in Mathematical Genetics. Main outcome and measures: Son of William Young and Christian Hay Yes Conclusions and relevance:
Yes Conflict of Interest Disclosures: Dr Joosten reported being a scientific founder of Trained Therapeutic Discovery and a scientific advisory board member of Olatec Therapeutics. Based on the only existing application of GREML-WGS [13], a sample size of ~40,000 would produce estimates precise enough to be statistically distinguished from other heritability estimates (Table 1).
Linear mixed model GWAS can account for more complicated patterns of stratification than PCA by modelling the effects of all genome-wide SNPs, rather than considering stratification along the major principal components alone, leading to reduced bias in SNP effect estimates compared to PCA adjustment [32]. In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. View Alexander Young’s profile on LinkedIn, the world's largest professional community.
Genealogy for Alexander Young (1719 - d.) family tree on Geni, with over 200 million profiles of ancestors and living relatives. (2)Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. Funding: AY was supported by a grant from the Li Ka Shing foundation (https://www.lksf.org/). Dr Netea reported being a scientific founder of Trained Therapeutic Discovery and receiving grants from ViiV HealthCare outside the submitted work. Therefore, there were many common variants with relatively weak effects on height that had been missed by GWAS due to a lack of statistical power.
2012 Dec;11(12):1048-56. doi: 10.1016/S1474-4422(12)70228-4. Is the Subject Area "Heredity" applicable to this article? However, the twin design makes several assumptions, most importantly that there is no greater environmental similarity of identical over non-identical twins. Walz L, Cohen AJ, Rebaza AP, Vanchieri J, Slade MD, Cruz CSD, Sharma L. Res Sq. Objective: To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.
One approach to answering this question is to extend the GREML methodology to high quality whole genome sequence (WGS) data[13], an extension that I’ll call GREML-WGS. It is likely that this challenge will be overcome shortly, since samples of similar magnitude already exist [16]. Population stratification presents another challenge for the GREML-WGS methodology. | No, Is the Subject Area "Genetics" applicable to this article? However, Sib-Regression requires hundreds of thousands of genotyped siblings pairs to obtain precise estimates. Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. Young AI(1)(2), Wauthier FL(3)(4), Donnelly P(5)(6). Brother of John Young; Grisel Young; Anna Young; Christian Young; William Young and 1 other; and Charles Young « less. Following degrees in Mathematics and Statistics and in Computational Biology at the University of Cambridge, Alex pursued a doctorate in Genomic Medicine and Statistics with Peter Donnelly at the Wellcome Trust Centre for Human Genetics, University of Oxford. PLoS Genet 15(6): An intermediate step towards this solution is to show how much variation we could hope to explain from all measured genetic variation, even if we do not have the statistical power to identify all of the specific causal variants. Father of William Young; Alexander Young; Christian Young and Girsel Young These estimates suggest that the heritability of height may be lower than estimated by twin studies.
It might appear that the advent of whole genome sequence data on tens of thousands of people is poised to resolve the issue, but here I want to sound a note of caution: more sequence data does not mean methodological problems go away…. For height, by 2010 around 40 variants had been identified that collectively explained around 5% of the variation in height, compared to a twin heritability of around 80% [5]. Alexander graduated from University Preparatory Charter School for Young Men, or UPrep. Parents. No, Is the Subject Area "Genetic polymorphism" applicable to this article? The school said he was a scholar athlete who "excelled not only in the classroom but also on the track and football field." Alexander I Young Richard Durbin Genetic association studies have explained only a small proportion of the estimated heritability of complex traits, leaving the remaining heritability 'missing'. The situation is even trickier for the rare variants used in GREML-WGS. Similar results have been obtained for other cognitive and behavioural traits [40, 41]. HHS No, Is the Subject Area "Twins" applicable to this article? genetic drift) will be correlated with the trait even though it has no causal effect on the trait. This work has shown that stratification can remain problematic even after attempting to correct for it using principal component analysis (PCA) [21], a technique that attempts to infer the major axes of genetic variation in a population (principal components), which are typically associated with geographic separation [22]. The methodology assumes that effect sizes are normally distributed within each bin, where the variants have been divided into bins based upon their frequency and the strength of their correlations with other variants (LD). In accordance with the planning of the University of Colorado, the 2020 IGSS conference will be held remotely this year.
I am interested in gene-gene and gene-environment interactions, as well as heritability estimation and the genetic basis of the family environment for traits like education. Typically, GREML restricts the analysis to distantly related individuals in order to avoid bias due to certain kinds of environmental effects shared between close relatives and genetic interactions [5,10]. The RDR and Sib-Regression estimates are from Icelandic samples, and the Swedish twin estimates are taken from various publications utilising the Swedish twin registry [27,33].
Alexander disease is a rare disorder of the nervous system.
Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. The information used to estimate heritability from rare variants by GREML-WGS comes from the variation in sharing of rare variants among distantly related pairs of individuals [13, 15]. Alexander Young family tree. 2020 Aug 11:2020.08.10.20172189. doi: 10.1101/2020.08.10.20172189.
It is hard to see how this type of stratification could be corrected for by PCA because it is specific to particular pairs or clusters of individuals who share a recent common ancestor. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NLM However, when the challenge of achieving sufficient precision of GREML-WGS estimates is overcome, questions about methodological assumptions remain. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. Supporting this, I have found evidence that the heritability of height in Iceland was overestimated by a method that is very similar to GREML [27], and I suspect that this overestimation was due in part to population stratification that had not been properly controlled for by PCA. However, if a pair of individuals share a very rare variant, then it is likely that they inherited this variant from a recent common ancestor, even if their genome-wide relatedness is low. The Sib-Regression estimate is 68% (S.E. Competing interests: The author declares that no competing interests exist. Siblings vary in their relatedness due to random inheritance of the same or different copies of parental chromosomes. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy. He pursued postdoctoral research with Augustine Kong at deCODE Genetics in Iceland and at the Big Data Institute at the University of Oxford.