A Systematic Review of Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

Exome sequencing has been commonly used to characterize rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) and searching for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to the heritability of complex clinical traits. We conducted a systematic review to find evidence supporting the use of EP strategies in the search for rare variants in genetic studies of complex diseases and highlight the contribution of rare variations to the genetic structure of polygenic conditions. After assessing the quality of the retrieved records, we selected 19 genetic studies considering EPs to demonstrate genetic association. All studies successfully identified several rare or de novo variants, and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach for patients with an early onset of a disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.

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A Systematic Review on Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

10.20944/preprints202007.0583.v1 ◽

2020 ◽

Author(s):

Sana Amanat ◽

Teresa Requena ◽

Jose Antonio Lopez-Escamez

Keyword(s):

Systematic Review ◽

Candidate Genes ◽

Rare Variants ◽

De Novo ◽

Complex Diseases ◽

De Novo Mutations ◽

Genetic Studies ◽

Complex Disorders ◽

Extreme Phenotype ◽

Age Related

Exome sequencing has been commonly used in rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) to search for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to heritability in complex clinical traits. We have conducted a systematic review to find evidence supporting the use of EP strategies to search for rare variants in genetic studies of complex diseases, to highlight the contribution of rare variation to the genetic structure of multiallelic conditions. After performing the quality assessment of the retrieved records, we selected 19 genetic studies considering EP to demonstrate genetic association. All the studies successfully identified several rare variants, de novo mutations and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach in patients with an early onset of the disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.

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De novo mutations implicate novel genes with burden of rare variants in Systemic Lupus Erythematosus

10.1101/139238 ◽

2017 ◽

Author(s):

Venu Pullabhatla ◽

Amy L. Roberts ◽

Myles J. Lewis ◽

Daniele Mauro ◽

David L. Morris ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Rare Variants ◽

De Novo ◽

Complex Diseases ◽

Phase Iii ◽

Disease Genes ◽

Systemic Lupus ◽

Extreme Phenotype ◽

Core Genes

AbstractThe omnigenic model of complex diseases stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing (WES), high-density imputation, and in vitro cellular assays, we identify three candidate core genes in the pathogenesis of Systemic Lupus Erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies (GWAS). In a follow-up cohort of 10,995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. We identify a burden of rare variants across PRKCD associated with SLE risk (P=0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P=0.0005 and P=0.0033). Both genes are functional candidates and significantly constrained against missense mutations in gene-level analyses, along with C1QTNF4. We further characterise the TNF-dependent functions of candidate gene C1QTNF4 on NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.Significance StatementRare variants, present in <1% in population, are expected to explain little of the heritability of complex diseases, such as Systemic Lupus Erythematosus (SLE), yet are likely to identify core genes crucial to disease mechanisms. Their rarity, however, limits the power to show their statistical association with disease. Through sequencing the exomes of SLE patients and their parents, we identified non-inherited de novo mutations in 14 genes and hypothesised that these are prime candidates for harbouring additional disease-associated rare variants. We demonstrate that two of these genes also carry a significant excess of rare variants in an independent, large cohort of SLE patients. Our findings will influence future study designs in the search for the ‘missing heritability’ of complex diseases.

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Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

10.1101/257758 ◽

2018 ◽

Author(s):

Lucilla Pizzo ◽

Matthew Jensen ◽

Andrew Polyak ◽

Jill A. Rosenfeld ◽

Katrin Mannik ◽

...

Keyword(s):

Family History ◽

Genetic Background ◽

Rare Variants ◽

De Novo ◽

Genetic Diagnosis ◽

Clinical Information ◽

Disease Genes ◽

Complete Evaluation ◽

Rare Cnvs ◽

Complex Disorders

AbstractPurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.MethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.ResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.ConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

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A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases

Journal of Medical Genetics ◽

10.1136/jmg.2004.024752 ◽

2005 ◽

Vol 42 (3) ◽

pp. 221-227 ◽

Cited By ~ 38

Author(s):

P-Y Liu

Keyword(s):

Candidate Genes ◽

Rare Variants ◽

Complex Diseases

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Penetrance estimation of SORL1 loss-of-function variants using a family-based strategy adjusted on APOE genotypes suggest a non-monogenic inheritance

10.1101/2021.06.30.450554 ◽

2021 ◽

Author(s):

Catherine Schramm ◽

Camille Charbonnier ◽

Aline Zaréa ◽

Morgane Lacour ◽

David Wallon ◽

...

Keyword(s):

Risk Factors ◽

Genetic Counseling ◽

Allele Frequency ◽

Rare Variants ◽

Rare Allele ◽

Loss Of Function ◽

Pedigree Data ◽

Complex Disorders ◽

Age Related ◽

Expectation Maximisation

For complex disorders, estimating the age-related penetrance associated with rare variants of strong effect is essential before a putative use for genetic counseling or disease prevention. However, rarity and co-occurrence with other risk factors make such estimations difficult. In the context of Alzheimer disease, we present a survival model to estimate the penetrance of SORL1 rare (allele frequency <1%) Loss-of-Function variants (LoF) while accounting for APOE-ε4, the main risk factor (allele frequency ~14% in Caucasians). We developed an efficient strategy to compute penetrance estimates accounting for both common and rare genetic variants based on available penetrance curves associated with common risk factors and using incomplete pedigree data to quantify the additional risk conferred by rare variants. Our model combines: (i) a baseline for non-carriers of SORL1 LoF variants, stratified by APOE genotypes derived from the Rotterdam study and (ii) an age-dependent proportional hazard effect for SORL1 LoF variants estimated from pedigrees with a proband carrying such a variant. We embed this model into an Expectation-Maximisation algorithm to accommodate for missing genotypes. Confidence intervals were computed by bootstraps. To correct for ascertainment bias, proband phenotypes were omitted. We obtained penetrance curves associated with SORL1 LoF variants at the digenic level. By age 70, we estimate a 100% penetrance of SORL1 LoF variants only among APOE-ε4ε4 carriers, while penetrance is 56% [40%-72%] among ε4 heterozygous carriers and 37% [26%-51%] among ε4 non-carriers. We conclude that rare SORL1 LoF variants should not be used for genetic counseling regardless of the APOE status.

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Changes in aqueous and vitreous inflammatory cytokine levels in neovascular age-related macular degeneration: A systematic review and meta-analysis

10.26226/morressier.5e61463c250f7ee26aeb41ed ◽

2020 ◽

Author(s):

Samuel Minaker

Keyword(s):

Systematic Review ◽

Macular Degeneration ◽

Inflammatory Cytokine ◽

Meta Analysis ◽

Age Related Macular Degeneration ◽

Age Related ◽

Cytokine Levels

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Faculty of 1000 evaluation for A systematic review on zinc for the prevention and treatment of age-related macular degeneration.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.718008525.793478652 ◽

2013 ◽

Author(s):

David Boyer

Keyword(s):

Systematic Review ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Age Related ◽

Prevention And Treatment

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Pathogenesis of Age-related Cataract: a systematic review of proteomic studies

Current Proteomics ◽

10.2174/1570164617999201020205100 ◽

2020 ◽

Vol 17 ◽

Author(s):

Christina Karakosta ◽

Argyrios Tzamalis ◽

Michalis Aivaliotis ◽

Ioannis Tsinopoulos

Keyword(s):

Systematic Review ◽

Oxidant Stress ◽

Critical Role ◽

Human Lens ◽

Nuclear Cataract ◽

Cataract Formation ◽

Post Translational Modification ◽

Ability To Act ◽

Age Related

Background/Objective:: The aim of this systematic review is to identify all the available data on human lens proteomics with a critical role to age-related cataract formation in order to elucidate the physiopathology of the aging lens. Materials and Methods:: We searched on Medline and Cochrane databases. The search generated 328 manuscripts. We included nine original proteomic studies that investigated human cataractous lenses. Results:: Deamidation was the major age-related post-translational modification. There was a significant increase in the amount of αA-crystallin D-isoAsp58 present at all ages, while an increase in the extent of Trp oxidation was apparent in cataract lenses when compared to aged normal lenses. During aging, enzymes with oxidized cysteine at critical sites included GAPDH, glutathione synthase, aldehyde dehydrogenase, sorbitol dehydrogenase, and PARK7. Conclusion:: D-isoAsp in αA crystallin could be associated with the development of age-related cataract in human, by contributing to the denaturation of a crystallin, and decreasing its ability to act as a chaperone. Oxidation of Trp may be associated with nuclear cataract formation in human, while the role of oxidant stress in age-related cataract formation is dominant.

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