The American Journal of Human Genetics This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Challenges of accurately estimating sex-biased admixture from X chromosomal and autosomal ancestry proportions
Sex-biased admixture can be inferred from ancestry-specific proportions of X chromosome and autosomes. In a paper published in the American Journal of Human Genetics, Micheletti et  al.1 used this approach to quantify male and female contributions following the transatlantic slave trade. Using a large dataset from 23andMe, they concluded that African and European contributions to gene pools in the Americas were much more sex biased than previously thought. We show that the re ported extreme sex-specific contributions can be attributed to unassigned genetic ancestry as well as the limitations of simple models of sex-biased...
Source: The American Journal of Human Genetics - February 2, 2023 Category: Genetics & Stem Cells Authors: Aaron Pfennig, Joseph Lachance Tags: Matters Arising Source Type: research

Using genetic association data to guide drug discovery and development: Review of methods and applications
Mendelian randomization exploits naturally occurring randomization in the transmission of genetic variants to mimic randomized trials in observational data. We review statistical methods and applications to showcase opportunities for applying Mendelian randomization in guiding pharmaceutical development efforts to target the right mechanism in the right population at the right time. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 2, 2023 Category: Genetics & Stem Cells Authors: Stephen Burgess, Amy M. Mason, Andrew J. Grant, Eric A.W. Slob, Apostolos Gkatzionis, Verena Zuber, Ashish Patel, Haodong Tian, Cunhao Liu, William G. Haynes, G. Kees Hovingh, Lotte Bjerre Knudsen, John C. Whittaker, Dipender Gill Tags: Review Source Type: research

This month in The Journal
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Source: The American Journal of Human Genetics - February 2, 2023 Category: Genetics & Stem Cells Authors: Kylee L. Spencer, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly
Pathogenic mutations in TTI1 (encoding a protein of the TTT complex) cause a rare autosomal-recessive disorder with a neurodevelopmental phenotype. These findings are important for diagnosis and genetic counseling; in addition, they provide the opportunity for development of potential therapies. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 31, 2023 Category: Genetics & Stem Cells Authors: Margaux Serey-Gaut, Marisol Cortes, Periklis Makrythanasis, Mohnish Suri, Alexander M.R. Taylor, Jennifer A. Sullivan, Ayat N. Asleh, Jaba Mitra, Mohamad A. Dar, Amy McNamara, Vandana Shashi, Sarah Dugan, Xiaofei Song, Jill A. Rosenfeld, Christelle Cabrol Tags: Article Source Type: research

The impact of 22q11.2 copy-number variants on human traits in the general population
Exploring the phenome-wide impact of 22q11.2 CNVs in the general population revealed variable effects of deletions and duplications of specific segments in the region. Mendelian randomization found the effect of the expression level of certain 22q11.2 genes to be concordant with the estimated CNV effect on the same trait. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 26, 2023 Category: Genetics & Stem Cells Authors: Mal ú Zamariolli, Chiara Auwerx, Marie C. Sadler, Adriaan van der Graaf, Kaido Lepik, Tabea Schoeler, Mariana Moysés-Oliveira, Anelisa G. Dantas, Maria Isabel Melaragno, Zoltán Kutalik Tags: Article Source Type: research

Significance tests for R2 of out-of-sample prediction using polygenic scores
R2 is a well-established measure for the reliability of polygenic score models although its significance test is rarely considered in this context. We release an R package r2redux that allows formal statistical comparison of two polygenic score models, providing the 95% confidence interval and significance of R2 difference. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 25, 2023 Category: Genetics & Stem Cells Authors: Md. Moksedul Momin, Soohyun Lee, Naomi R. Wray, S. Hong Lee Tags: Article Source Type: research

Loci for insulin processing and secretion provide insight into type 2 diabetes risk
Broadaway et  al. describe a genome-wide association meta-analysis in which they identify 36 proinsulin signals. Identification and integration of the proinsulin signals with glycemic traits, expression data in trait-relevant tissues, and functional follow-up provide hypotheses about potential mechanistic pathw ays for T2D loci. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 23, 2023 Category: Genetics & Stem Cells Authors: K. Alaine Broadaway, Xianyong Yin, Alice Williamson, Victoria A. Parsons, Emma P. Wilson, Anne H. Moxley, Swarooparani Vadlamudi, Arushi Varshney, Anne U. Jackson, Vasudha Ahuja, Stefan R. Bornstein, Laura J. Corbin, Graciela E. Delgado, Om P. Dwivedi, Li Tags: Article Source Type: research

Functional interpretation, cataloging, and analysis of 1,341 glucose-6-phosphate dehydrogenase variants
Interpreting the effect of sequence variation in G6PD can be used to predict which individuals are at risk for adverse drug reactions. By analyzing data from publications and databases, we provided interpretations for 186 G6PD variants of uncertain significance, bringing the total number of interpreted variants to 400. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 20, 2023 Category: Genetics & Stem Cells Authors: Renee C. Geck, Nicholas R. Powell, Maitreya J. Dunham Tags: Article Source Type: research

Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders
We present a user-friendly web application to detect pathogenic outlier gene expression and mRNA splicing in transcriptome data. Application of this pipeline in a cohort of 67 undiagnosed individuals with neurodevelopmental disorders increased the diagnostic yield by 13%. This approach will facilitate wider implementation of RNA-seq in routine genome diagnostics. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 19, 2023 Category: Genetics & Stem Cells Authors: Jordy Dekker, Rachel Schot, Michiel Bongaerts, Walter G. de Valk, Monique M. van Veghel-Plandsoen, Kathryn Monfils, Hannie Douben, Peter Elfferich, Esmee Kasteleijn, Leontine M.A. van Unen, Geert Geeven, Jasper J. Saris, Yvette van Ierland, Frans W. Verhe Tags: Article Source Type: research

Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing
We developed Paraphase, an informatics method that, combined with highly accurate long reads, can resolve the highly homologous SMN1/SMN2 genes involved in spinal muscular atrophy. We characterized SMN1/SMN2 haplotypes across populations and identified new genetic markers for silent carriers (2+0) with both copies of SMN1 on the same chromosome. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 19, 2023 Category: Genetics & Stem Cells Authors: Xiao Chen, John Harting, Emily Farrow, Isabelle Thiffault, Dalia Kasperaviciute, Genomics England Research Consortium, Alexander Hoischen, Christian Gilissen, Tomi Pastinen, Michael A. Eberle Tags: Article Source Type: research

Pathogen exposure misclassification can bias association signals in GWAS of infectious diseases when using population-based common control subjects
Pathogen exposure is a necessary but insufficient cause of infectious disease. Through simulation and empirical genome-wide association comparisons, Duchen et  al. show that ignoring pathogen exposure can bias genetic associations. Control selection is important to accurately characterize the genetics underlying outcomes conditional upon environmental exposures, including infectious diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 16, 2023 Category: Genetics & Stem Cells Authors: Dylan Duchen, Candelaria Vergara, Chloe L. Thio, Prosenjit Kundu, Nilanjan Chatterjee, David L. Thomas, Genevieve L. Wojcik, Priya Duggal Tags: Article Source Type: research

Epigenome-wide meta-analysis of BMI in nine cohorts: Examining the utility of epigenetically predicted BMI
DNA methylation is increasingly used as a biomarker of health and associates with BMI. Do et  al. constructed an epigenetic BMI score and observed differential metabolic health among individuals whose epigenetically predicted BMI deviates from their actual BMI. These findings suggest that epigenetic BMI prediction could provide information relevant to metabolic health. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 16, 2023 Category: Genetics & Stem Cells Authors: Whitney L. Do, Dianjianyi Sun, Karlijn Meeks, Pierre-Antoine Dugu é, Ellen Demerath, Weihua Guan, Shengxu Li, Wei Chen, Roger Milne, Abedowale Adeyemo, Charles Agyemang, Rami Nassir, JoAnn E. Manson, Aladdin H. Shadyab, Lifang Hou, Steve Horvath, Themist Tags: Article Source Type: research

15 years of GWAS discovery: Realizing the promise
We review how GWAS facilitated an impressive range of discoveries impacting multiple fields, including epidemiology, social science, and medicine. We predict that GWAS will continue to expand to more diverse populations and rarer variants, further improving our investigation into causes and consequences of human genetic variation for complex traits. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 11, 2023 Category: Genetics & Stem Cells Authors: Abdel Abdellaoui, Loic Yengo, Karin J.H. Verweij, Peter M. Visscher Tags: Review Source Type: research

Fast, accurate local ancestry inference with FLARE
Local ancestry is the ancestral origin at each point in the genome of an admixed individual. FLARE (fast local ancestry estimation) is a program for local ancestry inference that is highly accurate and computationally efficient. FLARE can analyze array and sequence data and can utilize large reference panels. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 6, 2023 Category: Genetics & Stem Cells Authors: Sharon R. Browning, Ryan K. Waples, Brian L. Browning Tags: Article Source Type: research

Unsupervised discovery of ancestry-informative markers and genetic admixture proportions in biobank-scale datasets
Admixture estimation plays a crucial role in ancestry inference and genome-wide association studies (GWASs). Computer programs such as ADMIXTURE and STRUCTURE are commonly employed to estimate the admixture proportions of sample individuals. However, these programs can be overwhelmed by the computational burdens imposed by the 105 to 106 samples and millions of markers commonly found in modern biobanks. An attractive strategy is to run these programs on a set of ancestry-informative SNP markers (AIMs) that exhibit substantially different frequencies across populations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 6, 2023 Category: Genetics & Stem Cells Authors: Seyoon Ko, Benjamin B. Chu, Daniel Peterson, Chidera Okenwa, Jeanette C. Papp, David H. Alexander, Eric M. Sobel, Hua Zhou, Kenneth L. Lange Tags: Article Source Type: research