Detecting gene-environment (G × E) interactions in the context of genome-wide association studies (GWAS) is a challenging problem since standard methods generally present a lack of power. An ...additional difficulty arises from the fact that the causal exposure is seldom observed and only a proxy of this exposure is observed. This leads to an additional drop in terms of power and it explains the failure of standard methods in detecting interactions, even very strong ones. In this article, we consider the latent exposure as a source of heterogeneity and we propose a new powerful method, named “Breakpoint Model for Logistic Regression” (BMLR), based on a breakpoint model, in order to detect G × E interactions when causal exposure is unobserved. First, the BMLR method is compared to the ordered-subset analysis for case-control method, which has been developed for the same purpose, through simulations. This highlights the ability of BMLR to detect the heterogeneity, and therefore, to detect interaction with latent exposure. Finally, the BMLR method is compared to standard methods, such as Plink, to perform a GWAS on a published realistic benchmark.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
In genetic diseases with variable age of onset, survival function estimation for the mutation carriers as well as estimation of the modifying factors effects are essential to provide individual risk ...assessment, both for mutation carriers management and prevention strategies. In practice, this survival function is classically estimated from pedigrees data where most genotypes are unobserved. In this article, we present a unifying Expectation-Maximization (EM) framework combining probabilistic computations in Bayesian networks with standard statistical survival procedures in order to provide mutation carrier survival estimates. The proposed approach allows to obtain previously published parametric estimates (e.g. Weibull survival) as particular cases as well as more general Kaplan-Meier non-parametric estimates, which is the main contribution. Note that covariates can also be taken into account using a proportional hazard model. The whole methodology is both validated on simulated data and applied to family samples with transthyretin-related hereditary amyloidosis (a rare autosomal dominant disease with highly variable age of onset), showing very promising results.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1. Manifestations ...may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified.
We sequenced POLE and POLD1 exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of POLE variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes.
Pathogenic POLE exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval CI: 4.2-17.5), 48.5% (33.2-60.3), and 74% (51.6-86.1). Cumulative risk of glioblastoma was 18.7% (3.2-25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site.
The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to POLE variant carriers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Transthyretin (TTR) familial amyloid polyneuropathies (FAP) are autosomal dominant devastating afflictions. They were first described in Portugal, later in Japan and Sweden and are now recognized ...worldwide. The TTR Val30Met mutation is the most common, and depending on the geographic origin, a wide variation in age at onset of the disease is observed. In Europe, northern Sweden is the second most prevalent area of the disease, and a late age of onset of 56 years has been reported. The present study aims to estimate the penetrance in TTR Val30Met Swedish families. Genealogical investigations, clinical data and genotyping were obtained in 77 TTR-Val30Met Swedish families. The penetrance in Val30Met carriers and variation within the endemic area, according to gender and transmitting parents were calculated by a newly developed bias-free method. The penetrance estimates were low, i.e. 1.7% and 22% at age 30 and 60 years, respectively, and far from complete (69%) by age 90 years. Differences between Piteå and Skellefteå regions were observed. Moreover, penetrance was significantly higher when the mutation was inherited from the mother than from the father. The low penetrance observed in TTR FAP kindreds and its variations is important information for the genetic counseling and treatment of Swedish FAP patients and their families.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In genetic diseases with variable age of onset, an accurate estimation of the survival function for the mutation carriers and also modifying factors effects estimations are important for the ...management of asymptomatic gene carriers across life. Among the modifying factors, the gender of the parent transmitting the mutation (i.e. the parent-of-origin effect) has been shown to have a significant effect on survival curve estimation on transthyretin familial amyloid polyneuropathy (ATTRv) families. However, as most genotypes are unknown, the parent-of-origin must be calculated through a probability estimated from the pedigree. We propose in this article to extend the method providing mutation carrier survival estimates in order to estimate the parent-of-origin effect. The method is both validated on simulated data and applied to familly samples with ATTRv.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hereditary transthyretin (ATTRv) amyloidosis is of autosomal dominant transmission, caused by a spectrum of mutations in the transthyretin (TTR) gene. The ATTRV30M (p.Val50Met) is the most frequent ...substitution in Europe. Northern Sweden is a known cluster for ATTRV30M amyloidosis patients due to high prevalence of the mutation rate, with homozygous cases. First symptoms occur generally during the 6th decade. Previous studies reported low penetrance in this area and possible anticipation in families. In order to refine our knowledge of the genetic aspects, penetrance and factors that influence the disease's risk, we performed a comprehensive study of ATTRV30M families in Sweden.
To assess anticipation, well-established age at onset (AO) was compared in all informative parent-offspring pairs and in subgroups, after excluding ascertainment biases. Penetrance was estimated using a non-parametric method that enables to study covariates' effect on the disease's risk.
We analysed 114 ATTRV30M Swedish families, including 12 homozygous individuals. Among 131 parent-offspring pairs, we found an average anticipation of 11.7 Standard Deviation (SD) =10.03 years, higher in case of maternal transmission (mean ± SD = 13.7 ± 8.4 years), compared to paternal transmission (mean ± SD = 7.9 ± 11.5 years, p < .003). Anticipation remained significant, after exclusion of ascertainment biases. In heterozygous ATTRV30M kindred, penetrance was low, estimated below 10% 95% confidence interval (CI) = 6-10 at 40 years-old, increasing to 71% 95% CI= 65-76 at age 90 years. The risk was found to be higher in male patients (p < .01) and in case of maternal transmission (p < .01), reflecting a parent of origin effect. We observed no difference of penetrance according the geographical origin. Finally, the disease risk was similar in heterozygous and homozygous ATTRV30M amyloidosis individuals.
Our study provides new data on the genetics of ATTRV30M families in Sweden, including the occurrence of anticipation and on penetrance. Both are increased in case of maternal inheritance and in male patients. Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area. Clinically, these findings are of importance to guide the management of sibships and the monitoring of mutation carriers.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Mediation analysis aims at disentangling the effects of a treatment on an outcome through alternative causal mechanisms and has become a popular practice in biomedical and social science ...applications. The causal framework based on counterfactuals is currently the standard approach to mediation, with important methodological advances introduced in the literature in the last decade, especially for simple mediation, that is with one mediator at the time. Among a variety of alternative approaches, Imai et al. showed theoretical results and developed an R package to deal with simple mediation as well as with multiple mediation involving multiple mediators conditionally independent given the treatment and baseline covariates. This approach does not allow to consider the often encountered situation in which an unobserved common cause induces a spurious correlation between the mediators. In this context, which we refer to as mediation with uncausally related mediators, we show that, under appropriate hypothesis, the natural direct and joint indirect effects are non-parametrically identifiable. Moreover, we adopt the quasi-Bayesian algorithm developed by Imai et al. and propose a procedure based on the simulation of counterfactual distributions to estimate not only the direct and joint indirect effects but also the indirect effects through individual mediators. We study the properties of the proposed estimators through simulations. As an illustration, we apply our method on a real data set from a large cohort to assess the effect of hormone replacement treatment on breast cancer risk through three mediators, namely dense mammographic area, nondense area and body mass index.
Background
SORL1 rare loss‐of‐function (LoF) variants are a strong risk factor for Alzheimer disease (AD) with odds ratios above 30 for protein‐truncating variants (PTVs). Accordingly, some pedigrees ...suggest a high penetrance with individuals developing AD before 65 years. However, the age‐dependent penetrance of these variants is unknown, precluding an accurate use for genetic counselling or inclusion in preventive trials. Importantly, both rarity of these variants and co‐occurrence with other risk factors, including the common APOE4 allele, make penetrance estimations difficult based on classical strategies.
Method
We selected LoF SORL1 rare variants (PTVs and missense variants with a LoF effect following in vitro analyses) from exome sequencing data of >1,300 EOAD cases from France (Rouen‐CNRMAJ). To evaluate the age‐related penetrance of AD associated with SORL1 LoF variants, we first built a model based on family information. To ensure an accurate adjustment for APOE genotypes, our model combines a literature‐based baseline for SORL1 non carriers to an additive effect of SORL1 LoF variants computed from our pedigrees. Since pedigrees include relatives with missing genotypes, we applied an Expectation‐Maximization (EM) algorithm to take full advantage of the available information. Probands’ phenotype information was excluded to avoid ascertainment biases. We applied this first method to 34 pedigrees (69 affected relatives, 270 unaffected relatives, 45 relatives with available genotype information). Additionally, we used sequencing data from 7306 cases and 5852 controls to compute a population‐based estimate of the age‐dependent lifetime risk associated with both APOE4 allele and SORL1 rare PTVs or predicted damaging missense variants.
Result
In both models, 100% penetrance was reached before 75 years for carriers of SORL1 LoF variants who were also homozygous for APOE4. Penetrance remained incomplete for heterozygous E4 carriers, even at age 75, and was lower for non‐E4 carriers. We are providing penetrance estimation curves and 95%IC for the first time for SORL1 rare variants and at the digenic level.
Conclusion
Our results suggest that SORL1 rare LoF variants should be considered in a non‐monogenic model, different from APP and PSEN1/2 mutations. Such curves appear critical before these variants are used for genetic counseling and preventive clinical trials.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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