Employed family-based genetic discovery combining linkage analysis and exome sequencing to identify RCL1 as a novel candidate gene for depression, with independent replication in a population-based cohort

Abstract With the advances of next-generation sequencing technology, the field of disease research has been revolutionized. However, pinpointing the disease-causing variants from millions of revealed variants is still a tough task. Here, we have reviewed the existing linkage analysis tools and presented PedMiner, a web-based application designed to narrow down candidate variants from family based whole-exome sequencing (WES) data through linkage analysis. PedMiner integrates linkage analysis, variant annotation and prioritization in one automated pipeline. It provides graphical visualization of the linked regions along with comprehensive annotation of variants and genes within these linked regions. This efficient and comprehensive application will be helpful for the scientific community working on Mendelian inherited disorders using family based WES data.

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Identifying the phenotypic effect of rare variants by including between-pedigree coancestry in variance components linkage analysis

10.1101/215863 ◽

2017 ◽

Author(s):

J.E. Hicks ◽

M. A. Province

Keyword(s):

Linkage Analysis ◽

Variance Components ◽

Rare Variants ◽

Simulated Data ◽

Population Based ◽

Pedigree Information ◽

Phenotypic Effect ◽

Sequencing Technologies ◽

Variance Components Analysis ◽

Family Based

AbstractThe contribution of rare variants to disease burden has become an important focus in genetic epidemiology. These effects are difficult to detect in population-based datasets, and as a result, interest in family-based study designs has resurfaced. Linkage analysis tools will need to be updated to accommodate the scale of data generated by modern genotyping and sequencing technologies.In conventional linkage analysis individuals in different pedigrees are assumed to be independent of each other. However, cryptic relatedness is often present in populations and haplotypes that harbor rare variants may be shared between pedigrees as well as within them.With millions of polymorphisms, Identity-by-descent (IBD) states across the genome can now be inferred without use of pedigree information. This is done by identifying long runs of identical-by-state genotypes which are unlikely to arise without IBD. Previously, IBD had to be estimated in pedigrees from recombination events in a sparse set of markers.We present a method for variance-components linkage that can incorporate large number of markers and allows for between-pedigree relatedness. We replace the IBD matrix generated from pedigree-based analysis with one generated from a genotype-based method. All pedigrees in a dataset are considered jointly, allowing between-pedigree IBD to be included in the model.In simulated data, we show that power is increased in the scenario when there is a haplotype shared IBD between members of different pedigrees. If there is no between-pedigree IBD, the analysis reduces to conventional variance-components analysis. By determining IBD states by long runs of dense IBS genotypes, linkage signals can be determined from their physical position, allowing more precise localization.

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Exome sequencing identified QRICH2 as a candidate gene responsible for stump-tailed sperm defects in Chinese consanguineous male offspring

Reproduction Abstracts ◽

10.1530/repabs.1.p250 ◽

2014 ◽

Author(s):

Huanxun Yue ◽

Dan Sun ◽

Huaqin Sun ◽

Wenming Xu

Keyword(s):

Candidate Gene ◽

Exome Sequencing ◽

Male Offspring

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Faculty Opinions recommendation of Linkage analysis combined with whole exome sequencing identifies a novel prothrombin (F2) gene mutation in a Dutch Caucasian family with unexplained thrombosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736729566.793568262 ◽

2019 ◽

Author(s):

Toshiyuki Miyata

Keyword(s):

Linkage Analysis ◽

Exome Sequencing ◽

Gene Mutation ◽

Whole Exome Sequencing ◽

Whole Exome ◽

Caucasian Family

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Case–Parent Trio Studies in Cleft Lip and Palate

Global Medical Genetics ◽

10.1055/s-0040-1722097 ◽

2020 ◽

Vol 07 (03) ◽

pp. 075-079

Author(s):

Mahamad Irfanulla Khan ◽

Prashanth CS

Keyword(s):

Genetic Variants ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Association Studies ◽

Geographical Location ◽

Genetic Association Studies ◽

Population Based ◽

Genome Wide Association Studies ◽

Family Based ◽

Study Designs

AbstractCleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations in humans involving various genetic and environmental risk factors. The prevalence of CL/P varies according to geographical location, ethnicity, race, gender, and socioeconomic status, affecting approximately 1 in 800 live births worldwide. Genetic studies aim to understand the mechanisms contributory to a phenotype by measuring the association between genetic variants and also between genetic variants and phenotype population. Genome-wide association studies are standard tools used to discover genetic loci related to a trait of interest. Genetic association studies are generally divided into two main design types: population-based studies and family-based studies. The epidemiological population-based studies comprise unrelated individuals that directly compare the frequency of genetic variants between (usually independent) cases and controls. The alternative to population-based studies (case–control designs) includes various family-based study designs that comprise related individuals. An example of such a study is a case–parent trio design study, which is commonly employed in genetics to identify the variants underlying complex human disease where transmission of alleles from parents to offspring is studied. This article describes the fundamentals of case–parent trio study, trio design and its significances, statistical methods, and limitations of the trio studies.

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Ketone body 3-hydroxybutyrate as a biomarker of aggression

Scientific Reports ◽

10.1038/s41598-021-84635-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

A. M. Whipp ◽

E. Vuoksimaa ◽

T. Korhonen ◽

R. Pool ◽

A. But ◽

...

Keyword(s):

Young Adults ◽

Ketone Body ◽

Ketone Bodies ◽

Population Based ◽

Resonance Spectroscopy ◽

Linear Regression Models ◽

Complex Behaviour ◽

Replication Sample ◽

Discovery Sample ◽

Independent Replication

AbstractHuman aggression is a complex behaviour, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983–1987, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the response variable and aggression ratings as predictor variables, and included several potential confounders. All metabolites showed low correlations with aggression, with only one—3-hydroxybutyrate, a ketone body produced during fasting—showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated (age 14) aggression were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher aggression (self-rated) was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.

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