Impact of inbreeding on fertility in a pre-industrial population

Robert, Alexandre; Toupance, Bruno; Tremblay, Marc Adélard; Heyer, Évelyne

doi:10.1038/ejhg.2008.237

Cited by 19 publications

(20 citation statements)

References 43 publications

(38 reference statements)

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“…Beyond methodological considerations, we confirmed in this study known associations between increased inbreeding and reduced lung function (PEF), cognitive ability (FIS and MTCIM), and fertility (NCF), which were previously reported, however, using different proxy traits (10,(29)(30)(31). We also replicated the association between inbreeding and decreased height (b UNI − LDMS: −1.71 phenotypic SD for complete inbreeding; P = 0.003) even though it was below the Bonferroni threshold.…”

Section: Discussionsupporting

confidence: 72%

Detection and quantification of inbreeding depression for complex traits from SNP data

Yengo

Zhu

Wray

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

106

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Quantifying the effects of inbreeding is critical to characterizing the genetic architecture of complex traits. This study highlights through theory and simulations the strengths and shortcomings of three SNP-based inbreeding measures commonly used to estimate inbreeding depression (ID). We demonstrate that heterogeneity in linkage disequilibrium (LD) between causal variants and SNPs biases ID estimates, and we develop an approach to correct this bias using LD and minor allele frequency stratified inference (LDMS). We quantified ID in 25 traits measured in ∼140,000 participants of the UK Biobank, using LDMS, and confirmed previously published ID for 4 traits. We find unique evidence of ID for handgrip strength, waist/hip ratio, and visual and auditory acuity (ID between −2.3 and −5.2 phenotypic SDs for complete inbreeding; P < 0.001). Our results illustrate that a careful choice of the measure of inbreeding combined with LDMS stratification improves both detection and quantification of ID using SNP data.M ating between close relatives has detrimental consequences on the survival and fertility of resulting offspring (1). This overall reduction of fitness, referred to as inbreeding depression (ID), is observable in a wide range of organisms, including plants (2), animals (3, 4), and humans (5). In humans, major abnormalities are more frequent in children from consanguineous marriages (6) and genes causing rare diseases can be mapped by ascertaining children from such matings (7). To date, although the genetic basis of ID is not completely elucidated, two main hypotheses are proposed to explain this phenomenon: homozygosity for partially recessive deleterious mutations and heterozygous advantage (overdominance) (1, 8). More generally, ID can be estimated for any complex trait, even if the trait is not an obvious component of fitness. For polygenic traits, ID can be detected if there is directional dominance (DD) across loci, which means that the phenotype of individuals who are heterozygous deviates from the average phenotypes of homozygous individuals in a consistent direction. For fitness components, DD is negative; i.e., on average homozygosity reduces fitness.In practice, ID can be estimated from pedigree studies when the relationships between parents are known (6, 9). However, given the limited number and the small sizes of such studies in humans, contemporary efforts (5, 10) to quantify ID have instead used SNP genotyping platforms to directly estimate inbreeding coefficients (F). SNP data may allow a more accurate evaluation of inbreeding (11), in particular for distant and cryptic inbreeding, and allow inference to be drawn from large population data (10). Conceptually, once a measure of F is derived from SNP data, ID can subsequently be estimated by correlating phenotype with the estimated F.Genome-wide estimators of F fall in two categories: average homozygosity measures across loci (irrespective of position) and measures of continuous runs of homozygosity (ROH). Using ROH, ID has been reported for diseas...

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Section: Discussionsupporting

confidence: 72%

Detection and quantification of inbreeding depression for complex traits from SNP data

Yengo

Zhu

Wray

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Previous studies have shown that IGF-1R overexpression or constitutive activation is sufficient to induce mammary tumor development in vivo [46]. Our analysis of IGF-1R expression in benign versus malignant breast tissue indicates a significantly higher level of IGF-1R positivity as defined by an Allred score of C7.…”

Section: Discussionmentioning

confidence: 98%

Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes

Yerushalmi

Gelmon

Leung

et al. 2011

Breast Cancer Res Treat

121

103

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Insulin-like growth factor-1 receptor (IGF-1R) is expressed in normal and malignant breast tissue and has been implicated in cell survival and resistance to cytotoxic therapies. We sought to assess the prognostic impact of IGF-1R expression among patients with early breast cancer and among breast cancer subtypes. Patients with stages I-III breast cancer with archival tumor tissue were included. Paraffin tissue blocks were used to construct a tissue microarray that was stained for ER, PR, Ki-67, HER2, EGFR, and cytokeratins 5/6 to classify the breast subgroups and for expression of IGF-1R, p27, and Bcl2 by immunohistochemistry. Kaplan-Meier plots were created by subtypes. Associations between IGF-1R and prognostic variables were examined in multivariate analysis. Among 2,871 eligible women the prognostic cut point for IGF-1R expression for breast-cancer-specific survival (BCSS) was Allred score < 7 versus ≥ 7. IGF-1R was ≥ 7 in 52% (LuminalA), 57.5% (LuminalB), 44.8% (LuminalHER2), 9.7% HER2-enriched, and 22.5% (Basal-like), P = 1.3 × 10(-52). IGF-1R+ was associated with age ≥ 50, lower histopathology grade, ER+, HER2 negativity (-), high p27 and high Bcl2 score. IGF-1R ≥ 7 was associated with better BCSS among LuminalB patients, hazard ratio = 0.64 (0.49-0.84); P = 1.2 × 10(-3,) and worse outcome in the HER2-enriched subtype, hazard ratio = 2.37 (1.21-4.64); P = 0.012. IGF-1R correlates with good prognostic markers among patients with early breast cancer and is differentially expressed with variable prognostic impact among breast cancer subtypes. Results may have relevance to the development of therapeutics targeting IGF-1R.

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“…As accurate as genome-wide assessments of inbreeding have proven, equally high-quality phenotype data are necessary to detect inbreeding depression. In humans and wild populations, inbreeding depression can be assessed by tracking vital rates--birth rate, mortality rate--in a population over time (Bittles et al, 2002;Robert et al, 2005;Robert et al, 2009;Johnson et al, 2011). In domestic species, additional measures of inbreeding depression include litter size, reproductive success, body size, and performance traits are used (as discussed earlier).…”

Section: Introductionmentioning

confidence: 99%

Inbreeding depression causes reduced fecundity in Golden Retrievers

Chu¹,

Simpson

Diehl

et al. 2019

Preprint

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Inbreeding depression has been demonstrated to impact vital rates, productivity, and performance in many domestic species. Many in the field have demonstrated the value of genomic measures of inbreeding compared to pedigree-based estimates of inbreeding; further, standardized, high-quality phenotype data on all individuals is invaluable for longitudinal analyses of a study cohort. We compared measures of reproductive fitness in a small cohort of Golden Retrievers enrolled in the Golden Retriever Lifetime Study (GRLS) to a genomic measurement of inbreeding, FROH. We demonstrate a statistically significant negative correlation between fecundity and FROH.This work sets the stage for larger scale analyses to investigate genomic regions associated with fecundity and other measures of fitness.

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Impact of inbreeding on fertility in a pre-industrial population

Cited by 19 publications

References 43 publications

Detection and quantification of inbreeding depression for complex traits from SNP data

Detection and quantification of inbreeding depression for complex traits from SNP data

Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes

Inbreeding depression causes reduced fecundity in Golden Retrievers

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