Cryptic Distant Relatives Are Common in Both Isolated and Cosmopolitan Genetic Samples

Henn, Brenna M.; Hon, Lawrence S.; Macpherson, J. Michael; Eriksson, Nicholas; Saxonov, Serge; Pe’er, Itsik; Mountain, Joanna L.

doi:10.1371/journal.pone.0034267

Cited by 200 publications

(238 citation statements)

References 41 publications

Supporting

Mentioning

235

Contrasting

Order By: Relevance

“…Each cohort was cleaned, imputed and analyzed separately to avoid batch effects. For each batch, we included subjects with genotyping call rates exceeding 99%; no related individuals based on identity by descent were included (12). From these individuals, any genotyped SNP with a call rate of at least 95%, minor allele frequency of 0.01 or greater and Hardy-Weinberg equilibrium p value < 1 × 10 -6 was included.…”

Section: Quality Control and Imputationmentioning

confidence: 99%

Efficient Genome-wide Association in Biobanks Using Topic Modeling Identifies Multiple Novel Disease Loci

McCoy

Castro

Snapper

et al. 2017

Mol Med

View full text Add to dashboard Cite

Section: Quality Control and Imputationmentioning

confidence: 99%

Efficient Genome-wide Association in Biobanks Using Topic Modeling Identifies Multiple Novel Disease Loci

McCoy

Castro

Snapper

et al. 2017

Mol Med

View full text Add to dashboard Cite

“…In practice, inferring the number of generations back to a common ancestor (k) is best accomplished through the signature of recent ancestry from the 22 autosomes, rather than through the short X chromosome. A number of methods are available for the task of estimating k through autosomal IBD segments (Huff et al 2011;Henn et al 2012;Durand et al 2014). Therefore, we concentrate on questions about the extra information that the X provides conditional on k being known with certainty.…”

Section: Inferencementioning

confidence: 99%

“…Various authors have used these types of results to derive likelihood-based models for classifying the genealogical relationship between pairs of individuals, using autosome IBD data (Huff et al 2011;Henn et al 2012;Durand et al 2014). …”

Section: Additional Autosomal Segment Distributionsmentioning

confidence: 99%

A Genealogical Look at Shared Ancestry on the X Chromosome

2016

View full text Add to dashboard Cite

Close relatives can share large segments of their genome identical by descent (IBD) that can be identified in genome-wide polymorphism data sets. There are a range of methods to use these IBD segments to identify relatives and estimate their relationship. These methods have focused on sharing on the autosomes, as they provide a rich source of information about genealogical relationships. We hope to learn additional information about recent ancestry through shared IBD segments on the X chromosome, but currently lack the theoretical framework to use this information fully. Here, we fill this gap by developing probability distributions for the number and length of X chromosome segments shared IBD between an individual and an ancestor k generations back, as well as between half-and full-cousin relationships. Due to the inheritance pattern of the X and the fact that X homologous recombination occurs only in females (outside of the pseudoautosomal regions), the number of females along a genealogical lineage is a key quantity for understanding the number and length of the IBD segments shared among relatives. When inferring relationships among individuals, the number of female ancestors along a genealogical lineage will often be unknown. Therefore, our IBD segment length and number distributions marginalize over this unknown number of recombinational meioses through a distribution of recombinational meioses we derive. By using Bayes' theorem to invert these distributions, we can estimate the number of female ancestors between two relatives, giving us details about the genealogical relations between individuals not possible with autosomal data alone.

show abstract

“…A maximal set of unrelated individuals was chosen for each analysis using a segmental identity-by-descent (IBD) estimation algorithm 39 . Individuals were defined as related if they shared more than 700 cM IBD, including regions where the two individuals share either one or both genomic segments identical-by-descent.…”

Section: Andme Datasetmentioning

confidence: 99%

Correcting subtle stratification in summary association statistics

Bhatia

Furlotte

Loh

et al. 2016

Preprint

View full text Add to dashboard Cite

Population stratification is a well-documented confounder in GWASes, and is often addressed by including principal component (PC) covariates computed from common SNPs (SNP-PCs). In our analyses of summary statistics from 36 GWASes (mean n=88k), including 20 GWASes using 23andMe data that included SNP-PC covariates, we observed a significantly inflated LD score regression (LDSC) intercept for several traits-suggesting that residual stratification remains a concern, even when SNP-PC covariates are included.Here we propose a new method, PC loading regression, to correct for stratification in summary statistics by leveraging SNP loadings for PCs computed in a large reference panel. In addition to SNP-PCs, the method can be applied to haploSNP-PCs, i.e. PCs computed from a larger number of rare haplotype variants that better capture subtle structure. Using simulations based on real genotypes from 54,000 individuals of diverse European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we show that PC loading regression effectively corrects for stratification along top PCs.We applied PC loading regression to several traits with inflated LDSC intercepts. Correcting for the top four SNP-PCs in GERA data, we observe a significant reduction in LDSC intercept height summary statistics from the Genetic Investigation of ANthropometric Traits (GIANT) consortium, but not for 23andMe summary statistics, which already included SNP-PC covariates. However, when correcting for additional haploSNP-PCs in 23andMe GWASes, inflation in the LDSC intercept was eliminated for eye color, hair color, and skin color and substantially reduced for height (1.41 to 1.16; n=430k). Correcting for haploSNP-PCs in GIANT height summary statistics eliminated inflation in the LDSC intercept (from 1.35 to 1.00; n=250k), eliminating 27 significant association signals including one at the LCT locus, which is highly differentiated among European populations and widely known to produce spurious signals. Overall, our results suggest that uncorrected population stratification is a concern in GWASes of large sample size and that PC loading regression can correct for this stratification.

show abstract

Cryptic Distant Relatives Are Common in Both Isolated and Cosmopolitan Genetic Samples

Cited by 200 publications

References 41 publications

Efficient Genome-wide Association in Biobanks Using Topic Modeling Identifies Multiple Novel Disease Loci

Efficient Genome-wide Association in Biobanks Using Topic Modeling Identifies Multiple Novel Disease Loci

A Genealogical Look at Shared Ancestry on the X Chromosome

Correcting subtle stratification in summary association statistics

Contact Info

Product

Resources

About