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Journal of the American Association of... Jul 2020Genetics is now known to play a substantial role in the predisposition to obesity and may contribute up to 70% risk for the disease. Over a hundred genes and gene...
Genetics is now known to play a substantial role in the predisposition to obesity and may contribute up to 70% risk for the disease. Over a hundred genes and gene variants related to excess weight have been discovered. Yet, genetic obesity risk does not always translate into actual obesity development, suggesting complex interactions between genetic, behavioral, and environmental influences and resulting epigenetic changes. Rare but serious forms of monogenic obesity typically appear in early childhood. Polygenic obesity is most common and demonstrates strong interplay between genes and the obesogenic environment. This review provides an overview of genetic causes of obesity, potential mechanisms of epigenetic changes, and environmental influences that should diminish obesity bias and offer hope for more effective obesity prevention and intervention strategies.
Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Humans; Multifactorial Inheritance; Obesity; United States
PubMed: 32658169
DOI: 10.1097/JXX.0000000000000447 -
Pigment Cell & Melanoma Research Jan 2020Vitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair. Genome-wide linkage studies and genome-wide... (Review)
Review
Vitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair. Genome-wide linkage studies and genome-wide association studies in European ancestry cases identified over 50 vitiligo susceptibility loci, defining a model of melanocyte-directed autoimmunity. Vitiligo heritability is exceedingly high, ~2/3 coming from common and ~1/3 from rare genomic variants; ~20% of vitiligo risk is environmental. Vitiligo genetic risk is polygenic, with greater additive risk in multiplex vitiligo families than simplex cases. Vitiligo age-of-onset is bimodal, also involving a major genetic component; a MHC enhancer haplotype confers extreme risk for vitiligo (OR 8.1) and early disease onset, increasing expression of HLA-DQB1 mRNA and HLA-DQ protein and thus perhaps facilitating presentation of triggering antigens. Vitiligo triggering also involves a major environmental component; dramatic delay in vitiligo age-of-onset, especially from 1973 to 2004, suggests that exposure or response to a key vitiligo environmental trigger diminished during this period. Together, these findings provide deep understanding of vitiligo pathogenesis and genetic architecture, suggesting that vitiligo represents a tractable model for investigating complex disease genetic architecture and predictive aspects of personalized medicine.
Topics: Age of Onset; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Risk Factors; Vitiligo
PubMed: 31743585
DOI: 10.1111/pcmr.12848 -
Science (New York, N.Y.) Sep 2021
Topics: Disease; Genetics, Medical; Genome, Human; Human Genome Project; Humans; Multifactorial Inheritance; Mutation
PubMed: 34554809
DOI: 10.1126/science.abm1359 -
Human Genomics Mar 2023Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid...
BACKGROUND
Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH.
MATERIALS AND METHODS
We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test.
RESULTS
In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls.
CONCLUSION
Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.
Topics: Female; Pregnancy; Humans; Multifactorial Inheritance; Mutation; Hydrocephalus; Consanguinity; Databases, Factual
PubMed: 36859317
DOI: 10.1186/s40246-023-00464-w -
Journal of Experimental Botany Jan 2021
Topics: Multifactorial Inheritance; Photosynthesis; Plant Leaves
PubMed: 33471904
DOI: 10.1093/jxb/eraa498 -
BMC Musculoskeletal Disorders Apr 2020Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely...
BACKGROUND
Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity.
METHODS
We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis.
RESULTS
We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls.
CONCLUSIONS
Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.
Topics: Adolescent; Adult; Case-Control Studies; Cervical Vertebrae; Child; Child, Preschool; Female; Humans; Klippel-Feil Syndrome; Male; Multifactorial Inheritance; Mutation; Pedigree; Radiography; Transcription Factors; Young Adult
PubMed: 32278351
DOI: 10.1186/s12891-020-03229-x -
Journal of Advanced Nursing Aug 2019
Topics: Female; Genetic Predisposition to Disease; Humans; Male; Multifactorial Inheritance; Nurse-Patient Relations
PubMed: 30950539
DOI: 10.1111/jan.14020 -
Molecules and Cells Jan 2024
Topics: Multifactorial Inheritance
PubMed: 38376484
DOI: 10.1016/j.mocell.2023.10.002 -
Genes Sep 2023Non-syndromic cleft lip with or without palate (NSCL/P) is a prevalent birth defect that affects 1/500-1/1400 live births globally. The genetic basis of NSCL/P is... (Review)
Review
Non-syndromic cleft lip with or without palate (NSCL/P) is a prevalent birth defect that affects 1/500-1/1400 live births globally. The genetic basis of NSCL/P is intricate and involves both genetic and environmental factors. In the past few years, various genetic inheritance models have been proposed to elucidate the underlying mechanisms of NSCL/P. These models range from simple monogenic inheritance to more complex polygenic inheritance. Here, we present a comprehensive overview of the genetic inheritance model of NSCL/P exemplified by representative genes and regions from both monogenic and polygenic perspectives. We also summarize existing association studies and corresponding loci of NSCL/P within the Chinese population and highlight the potential of utilizing polygenic risk scores for risk stratification of NSCL/P. The potential application of polygenic models offers promising avenues for improved risk assessment and personalized approaches in the prevention and management of NSCL/P individuals.
Topics: Humans; Cleft Lip; Cleft Palate; Multifactorial Inheritance; Inheritance Patterns
PubMed: 37895208
DOI: 10.3390/genes14101859 -
Trends in Genetics : TIG Jun 2023The burden of human disease lies predominantly in polygenic diseases. Since the early 2000s, genome-wide association studies (GWAS) have identified genetic variants and... (Review)
Review
The burden of human disease lies predominantly in polygenic diseases. Since the early 2000s, genome-wide association studies (GWAS) have identified genetic variants and loci associated with complex traits. These have ranged from variants in coding sequences to mutations in regulatory regions, such as promoters and enhancers, as well as mutations affecting mediators of mRNA stability and other downstream regulators, such as 5' and 3'-untranslated regions (UTRs), long noncoding RNA (lncRNA), and miRNA. Recent research advances in genetics have utilized a combination of computational techniques, high-throughput in vitro and in vivo screening modalities, and precise genome editing to impute the function of diverse classes of genetic variants identified through GWAS. In this review, we highlight the vastness of genomic variants associated with polygenic disease risk and address recent advances in how genetic tools can be used to functionally characterize them.
Topics: Humans; Genome-Wide Association Study; Multifactorial Inheritance; Genetic Predisposition to Disease; Genetic Variation; Genomics
PubMed: 36997428
DOI: 10.1016/j.tig.2023.02.014