Identification of shared extended haplotypes in both population-based studies of complex disease and family-based studies of Mendelian disorders

Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500–5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.

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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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Protocol for the Process Evaluation of a Complex, Statewide Intervention to Reduce Salt Intake in Victoria, Australia

Nutrients ◽

10.3390/nu10080998 ◽

2018 ◽

Vol 10 (8) ◽

pp. 998 ◽

Cited By ~ 4

Author(s):

Kathy Trieu ◽

Stephen Jan ◽

Mark Woodward ◽

Carley Grimes ◽

Bruce Bolam ◽

...

Keyword(s):

Process Evaluation ◽

Complex Disease ◽

Salt Intake ◽

Complex Interventions ◽

Reduction Process ◽

Population Based ◽

Structured Interviews ◽

Salt Reduction ◽

Campaign Evaluation ◽

Reduced Salt

Systematic reviews of trials consistently demonstrate that reducing salt intake lowers blood pressure. However, there is limited evidence on how interventions function in the real world to achieve sustained population-wide salt reduction. Process evaluations are crucial for understanding how and why an intervention resulted in its observed effect in that setting, particularly for complex interventions. This project presents the detailed protocol for a process evaluation of a statewide strategy to lower salt intake in Victoria, Australia. We describe the pragmatic methods used to collect and analyse data on six process evaluation dimensions: reach, dose or adoption, fidelity, effectiveness, context and cost, informed by Linnan and Steckler’s framework and RE-AIM. Data collection methods include routinely collected administrative data; surveys of processed foods, the population, food industry and organizations; targeted campaign evaluation and semi-structured interviews. Quantitative and qualitative data will be triangulated to provide validation or context for one another. This process evaluation will contribute new knowledge about what components of the intervention are important to salt reduction strategies and how the interventions cause reduced salt intake, to inform the transferability of the program to other Australian states and territories. This protocol can be adapted for other population-based, complex, disease prevention interventions.

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IBD5 IS STRONGLY ASSOCIATED WITH PEDIATRIC ONSET CROHN??S DISEASE (CD): CONFIRMATION BY FAMILY-BASED ASSOCIATION & CASE CONTROL ANALYSIS FROM A PROSPECTIVE POPULATION-BASED NORTH AMERICAN COHORT

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/01.mpg.0000182027.68806.43 ◽

2005 ◽

Vol 41 (4) ◽

pp. 545-546

Author(s):

Subra Kugathasan ◽

U Babusukumar ◽

E McGuire ◽

T Wang ◽

J Nebel ◽

...

Keyword(s):

North American ◽

Population Based ◽

Case Control ◽

Control Analysis ◽

Family Based ◽

Case Control Analysis ◽

North American Cohort ◽

Pediatric Onset

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PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses

Journal of Human Genetics ◽

10.1007/s10038-005-0319-8 ◽

2005 ◽

Vol 51 (1) ◽

pp. 38-46 ◽

Cited By ~ 33

Author(s):

Eisaburo Ichikawa ◽

Akira Watanabe ◽

Yoko Nakano ◽

Sadanori Akita ◽

Akiyoshi Hirano ◽

...

Keyword(s):

Cleft Palate ◽

Candidate Gene ◽

Japanese Population ◽

Cleft Lip ◽

Population Based ◽

Family Based

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On the Estimation of Heritability with Family-Based and Population-Based Samples

BioMed Research International ◽

10.1155/2015/671349 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Youngdoe Kim ◽

Young Lee ◽

Sungyoung Lee ◽

Nam Hee Kim ◽

Jeongmin Lim ◽

...

Keyword(s):

Blood Pressure ◽

Large Scale ◽

Density Lipoprotein ◽

Population Based ◽

Variance Component Analysis ◽

Polygenic Effect ◽

Relationship Matrix ◽

Phenotypic Variance ◽

Heritability Estimates ◽

Family Based

For a family-based sample, the phenotypic variance-covariance matrix can be parameterized to include the variance of a polygenic effect that has then been estimated using a variance component analysis. However, with the advent of large-scale genomic data, the genetic relationship matrix (GRM) can be estimated and can be utilized to parameterize the variance of a polygenic effect for population-based samples. Therefore narrow sense heritability, which is both population and trait specific, can be estimated with both population- and family-based samples. In this study we estimate heritability from both family-based and population-based samples, collected in Korea, and the heritability estimates from the pooled samples were, for height, 0.60; body mass index (BMI), 0.32; log-transformed triglycerides (log TG), 0.24; total cholesterol (TCHL), 0.30; high-density lipoprotein (HDL), 0.38; low-density lipoprotein (LDL), 0.29; systolic blood pressure (SBP), 0.23; and diastolic blood pressure (DBP), 0.24. Furthermore, we found differences in how heritability is estimated—in particular the amount of variance attributable to common environment in twins can be substantial—which indicates heritability estimates should be interpreted with caution.

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