scholarly journals LD scores are associated with differences in allele frequencies between populations but LD score regression can still distinguish confounding from polygenicity

2019 ◽  
Author(s):  
Mason Alexander ◽  
David Curtis
Keyword(s):  
Allele Frequency ◽  
Population Stratification ◽  
Case Control ◽  
Regression Method ◽  
Allele Frequencies ◽  
Polygenic Effect ◽  
Chi Squared ◽  
Hapmap Populations ◽  
Large Case ◽  
Control Samples

SummaryThe LD score regression method tests whether there is an association between the LD score and allele frequency differences between cases and controls. It makes the assumption that there is no association between LD score and allele frequency differences between populations and hence that any observed association is due to a polygenic effect rather than population stratification. This assumption has not previously been tested. In comparisons between HapMap populations we observe that there is indeed an association between the LD score and allele frequency differences. However this effect is small and when we carry out simulations of large case-control samples the effect becomes negligible. We conclude that if the intercept is small then any increase in mean chi-squared does indeed reflect a polygenic effect rather than population stratification.

scholarly journals Identifying loci with different allele frequencies among cases of eight psychiatric disorders using CC-GWAS

2020 ◽  
Author(s):  
Wouter J. Peyrot ◽  
Alkes L. Price
Keyword(s):  
Psychiatric Disorders ◽  
Allele Frequency ◽  
Case Control ◽  
Genetic Differences ◽  
Allele Frequencies ◽  
Effective Control ◽  
Type I ◽  
Summary Statistics ◽  
Compulsive Disorder ◽  
Genome Wide

AbstractPsychiatric disorders are highly genetically correlated, and many studies have focused on their shared genetic components. However, little research has been conducted on the genetic differences between psychiatric disorders, because case-case comparisons of allele frequencies among cases currently require individual-level data from cases of both disorders. We developed a new method (CC-GWAS) to test for differences in allele frequency among cases of two different disorders using summary statistics from the respective case-control GWAS; CC-GWAS relies on analytical assessments of the genetic distance between cases and controls of each disorder. Simulations and analytical computations confirm that CC-GWAS is well-powered and attains effective control of type I error. In particular, CC-GWAS identifies and discards false positive associations that can arise due to differential tagging of a shared causal SNP (with the same allele frequency in cases of both disorders), e.g. due to subtle differences in ancestry between the input case-control studies. We applied CC-GWAS to publicly available summary statistics for schizophrenia, bipolar disorder and major depressive disorder, and identified 116 independent genome-wide significant loci distinguishing these three disorders, including 21 CC-GWAS-specific loci that were not genome-wide significant in the input case-control summary statistics. Two of the CC-GWAS-specific loci implicate the genes KLF6 and KLF16 from the Kruppel-like family of transcription factors; these genes have been linked to neurite outgrowth and axon regeneration. We performed a broader set of case-case comparisons by additionally analyzing ADHD, anorexia nervosa, autism, obsessive-compulsive disorder and Tourette’s Syndrome, yielding a total of 196 independent loci distinguishing eight psychiatric disorders, including 72 CC-GWAS-specific loci. We confirmed that loci identified by CC-GWAS replicated convincingly in applications to data sets for which independent replication data were available. In conclusion, CC-GWAS robustly identifies loci with different allele frequencies among cases of different disorders using results from the respective case-control GWAS, providing new insights into the genetic differences between eight psychiatric disorders.

scholarly journals Estimation of Cry3Bb1 resistance allele frequency in field populations of western corn rootworm using a genetic marker

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alan Willse ◽  
Lex Flagel ◽  
Graham Head
Keyword(s):  
Allele Frequency ◽  
Western Corn Rootworm ◽  
Allele Frequencies ◽  
Chromosome 8 ◽  
Corn Belt ◽  
Corn Rootworm ◽  
Resistance Allele ◽  
Response To Selection ◽  
The Us ◽  
Causal Allele

Abstract Following the discovery of western corn rootworm (WCR; Diabrotica virgifera virgifera) populations resistant to the Bacillus thuringiensis (Bt) protein Cry3Bb1, resistance was genetically mapped to a single locus on WCR chromosome 8 and linked SNP markers were shown to correlate with the frequency of resistance among field-collected populations from the US Corn Belt. The purpose of this paper is to further investigate the relationship between one of these resistance-linked markers and the causal resistance locus. Using data from laboratory bioassays and field experiments, we show that one allele of the resistance-linked marker increased in frequency in response to selection, but was not perfectly linked to the causal resistance allele. By coupling the response to selection data with a genetic model of the linkage between the marker and the causal allele, we developed a model that allowed marker allele frequencies to be mapped to causal allele frequencies. We then used this model to estimate the resistance allele frequency distribution in the US Corn Belt based on collections from 40 populations. These estimates suggest that chromosome 8 Cry3Bb1 resistance allele frequency was generally low (<10%) for 65% of the landscape, though an estimated 13% of landscape has relatively high (>25%) resistance allele frequency.

scholarly journals A simple method to estimate the in-house limit of detection for genetic mutations with low allele frequencies in whole-exome sequencing analysis by next-generation sequencing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Takumi Miura ◽  
Satoshi Yasuda ◽  
Yoji Sato
Keyword(s):  
Next Generation Sequencing ◽  
Allele Frequency ◽  
Somatic Mutations ◽  
Limit Of Detection ◽  
Allele Frequencies ◽  
Genetic Mutations ◽  
Sequencing Data ◽  
Simple Method ◽  
Whole Exome ◽  
Generation Sequencing

Abstract Background Next-generation sequencing (NGS) has profoundly changed the approach to genetic/genomic research. Particularly, the clinical utility of NGS in detecting mutations associated with disease risk has contributed to the development of effective therapeutic strategies. Recently, comprehensive analysis of somatic genetic mutations by NGS has also been used as a new approach for controlling the quality of cell substrates for manufacturing biopharmaceuticals. However, the quality evaluation of cell substrates by NGS largely depends on the limit of detection (LOD) for rare somatic mutations. The purpose of this study was to develop a simple method for evaluating the ability of whole-exome sequencing (WES) by NGS to detect mutations with low allele frequency. To estimate the LOD of WES for low-frequency somatic mutations, we repeatedly and independently performed WES of a reference genomic DNA using the same NGS platform and assay design. LOD was defined as the allele frequency with a relative standard deviation (RSD) value of 30% and was estimated by a moving average curve of the relation between RSD and allele frequency. Results Allele frequencies of 20 mutations in the reference material that had been pre-validated by droplet digital PCR (ddPCR) were obtained from 5, 15, 30, or 40 G base pair (Gbp) sequencing data per run. There was a significant association between the allele frequencies measured by WES and those pre-validated by ddPCR, whose p-value decreased as the sequencing data size increased. By this method, the LOD of allele frequency in WES with the sequencing data of 15 Gbp or more was estimated to be between 5 and 10%. Conclusions For properly interpreting the WES data of somatic genetic mutations, it is necessary to have a cutoff threshold of low allele frequencies. The in-house LOD estimated by the simple method shown in this study provides a rationale for setting the cutoff.

scholarly journals The Dynamics of Gynodioecy in Plantago lanceolatu L. II. Mode of Action and Frequencies of Restorer Alleles

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1317-1328
Author(s):  
Anita A de Haan ◽  
Hans P Koelewijn ◽  
Maria P J Hundscheid ◽  
Jos M M Van Damme
Keyword(s):  
Cytoplasmic Male Sterility ◽  
Male Sterility ◽  
Allele Frequency ◽  
Mode Of Action ◽  
Male Fertility ◽  
Fertility Restoration ◽  
Plantago Lanceolata ◽  
Allele Frequencies ◽  
Male Sterile ◽  
Male Fertility Restoration

Male fertility in Plantago lanceolata is controlled by the interaction of cytoplasmic and nuclear genes. Different cytoplasmic male sterility (CMS) types can be either male sterile or hermaphrodite, depending on the presence of nuclear restorer alleles. In three CMS types of P. lanceolata (CMSI, CMSIIa, and CMSIIb) the number of loci involved in male fertility restoration was determined. In each CMS type, male fertility was restored by multiple genes with either dominant or recessive action and capable either of restoring male fertility independently or in interaction with each other (epistasis). Restorer allele frequencies for CMSI, CMSIIa and CMSIIb were determined by crossing hermaphrodites with “standard” male steriles. Segregation of male steriles vs. non-male steriles was used to estimate overall restorer allele frequency. The frequency of restorer alleles was different for the CMS types: restorer alleles for CMSI were less frequent than for CMSIIa and CMSIIb. On the basis of the frequencies of male steriles and the CMS types an “expected” restorer allele frequency could be calculated. The correlation between estimated and expected restorer allele frequency was significant.

scholarly journals Dietary N-nitroso compounds and risk of pancreatic cancer: results from a large case–control study

2018 ◽  
Vol 40 (2) ◽  
pp. 254-262 ◽  
Author(s):  
Jiali Zheng ◽  
Janice Stuff ◽  
Hongwei Tang ◽  
Manal M Hassan ◽  
Carrie R Daniel ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Case Control Study ◽  
Case Control ◽  
Nitroso Compounds ◽  
Control Study ◽  
Large Case

scholarly journals Allele frequency divergence reveals ubiquitous influence of positive selection in Drosophila

2021 ◽  
Author(s):  
Jason Bertram
Keyword(s):  
Allele Frequency ◽  
Evolutionary Biology ◽  
Polymorphic Locus ◽  
Purifying Selection ◽  
Allele Frequencies ◽  
Intermediate Allele ◽  
Genome Wide ◽  
Signature Of Selection ◽  
Basic Objective ◽  
Genomic Regions

Resolving the role of natural selection is a basic objective of evolutionary biology. It is generally difficult to detect the influence of selection because ubiquitous non-selective stochastic change in allele frequencies (genetic drift) degrades evidence of selection. As a result, selection scans typically only identify genomic regions that have undergone episodes of intense selection. Yet it seems likely such episodes are the exception; the norm is more likely to involve subtle, concurrent selective changes at a large number of loci. We develop a new theoretical approach that uncovers a previously undocumented genome-wide signature of selection in the collective divergence of allele frequencies over time. Applying our approach to temporally-resolved allele frequency measurements from laboratory and wild Drosophila populations, we quantify the selective contribution to allele frequency divergence and find that selection has substantial effects on much of the genome. We further quantify the magnitude of the total selection coefficient (a measure of the combined effects of direct and linked selection) at a typical polymorphic locus, and find this to be large (of order 1%) even though most mutations are not directly under selection. We find that selective allele frequency divergence is substantial at intermediate allele frequencies, which we argue is most parsimoniously explained by positive --- not purifying --- selection. Thus, in these populations most mutations are far from evolving neutrally in the short term (tens of generations), including mutations with neutral fitness effects, and the result cannot be explained simply as a purging of deleterious mutations.

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