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Annals of Neurology Jul 2021The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.
OBJECTIVE
The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.
METHODS
We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.
RESULTS
A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.
INTERPRETATION
This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
Topics: Aged; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Middle Aged; Mutation; Parkinson Disease; Penetrance
PubMed: 33938021
DOI: 10.1002/ana.26094 -
International Journal of Molecular... Jan 2021Missense mutations in the gene were first identified as a pathogenic cause of Parkinson's disease (PD) in 2004. Soon thereafter, a founder mutation in , p.G2019S... (Review)
Review
Missense mutations in the gene were first identified as a pathogenic cause of Parkinson's disease (PD) in 2004. Soon thereafter, a founder mutation in , p.G2019S (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide carrying this risk variant. While the clinical presentation of LRRK2 parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology, including a large proportion of cases with concomitant Alzheimer's pathology, hailing LRRK2 parkinsonism as the "Rosetta stone" of parkinsonian disorders, which provides clues to an understanding of the different neuropathological trajectories. These differences may result from interactions between the LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function and, thereby, influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of LRRK2 parkinsonism. We review which genetic modifiers of LRRK2 influence clinical symptoms, age at onset, and penetrance, what LRRK2 mutations are associated with pleomorphic LRRK2 neuropathology, and which environmental modifiers can augment LRRK2 mutant pathophysiology. Understanding how function is influenced and modulated by other interactors and environmental factors-either increasing toxicity or providing resilience-will inform targeted therapeutic development in the years to come. This will allow the development of disease-modifying therapies for PD- and -related neurodegeneration.
Topics: Age Factors; Alleles; Animals; Disease Susceptibility; Environment; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Incidence; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Multifactorial Inheritance; Mutation; Neurodegenerative Diseases; Parkinsonian Disorders; Penetrance; Phenotype
PubMed: 33494262
DOI: 10.3390/ijms22031045 -
Annals of Clinical and Translational... May 2023To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.
OBJECTIVE
To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.
METHODS
Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE-ε4 carriers and non-carriers.
RESULTS
PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE-ε4 allele (OR = 1.74 [1.53-1.91]) compared with APOE-ε4 carriers (1.53 [1.4-1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e-05). Stratifying by APOE-ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE-ε4 carriers (14.5% higher at age 80, p = 0.002) and non-carriers (26% higher at 80, p < 10e-05). Recurrence risk for siblings conferred by a co-sibling in the highest PRS quintile increased from 4% between the ages of 65-74 years to 39% at age 85 and older.
INTERPRETATION
PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non-carries of APOE-ε4.
Topics: Humans; Aged; Aged, 80 and over; Alzheimer Disease; Penetrance; Bayes Theorem; Risk Factors; Apolipoproteins E
PubMed: 36946865
DOI: 10.1002/acn3.51757 -
Molecular Psychiatry Jan 2023Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental... (Review)
Review
Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype-phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics.
Topics: Animals; Humans; DiGeorge Syndrome; Schizophrenia; Autistic Disorder; Autism Spectrum Disorder; Phenotype
PubMed: 36192458
DOI: 10.1038/s41380-022-01783-5 -
Genes Sep 2021Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in , however a significant proportion of mutation carriers do not develop retinopathy. Here, we...
Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in , however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between polymorphism, repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized and expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C>T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy repeat in the promoter, while 3/5 NPCs carried a 4-copy repeat. The rs4806718 genotype did not correlate with disease penetrance. expression declined with age in adult cadaveric retina. and expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy repeat, but not with polymorphisms.
Topics: Adolescent; Adult; Aged; Cells, Cultured; Child; Eye Proteins; Female; Genes, Modifier; Humans; Male; Middle Aged; Penetrance; Polymorphism, Genetic; Retina; Retinitis Pigmentosa; Scavenger Receptors, Class A; Transcription Factors
PubMed: 34680937
DOI: 10.3390/genes12101542 -
Journal of Surgical Oncology Jun 2022Germline CDH1 defects are related with the development of multiple cancers due its pleiotropic nature. These several conditions are associated with various risks of... (Review)
Review
Germline CDH1 defects are related with the development of multiple cancers due its pleiotropic nature. These several conditions are associated with various risks of penetrance and with different clinical management strategies. In this clinical review, we described the penetrance risks of gastric, breast, prostate, and colorectal cancers, in CDH1 carriers, within as well as outside the familial setting, and the best approaches to manage each risk, using either prophylactic surgery or surveillance.
Topics: Antigens, CD; Cadherins; Genetic Predisposition to Disease; Germ Cells; Germ-Line Mutation; Heterozygote; Humans; Male; Penetrance; Stomach Neoplasms
PubMed: 35277969
DOI: 10.1002/jso.26847 -
Genetics and Molecular Biology 2022Precision Medicine emerges from the genomic paradigm of health and disease. For precise molecular diagnoses of genetic diseases, we must analyze the Whole Exome (WES) or...
Precision Medicine emerges from the genomic paradigm of health and disease. For precise molecular diagnoses of genetic diseases, we must analyze the Whole Exome (WES) or the Whole Genome (WGS). By not needing exon capture, WGS is more powerful to detect single nucleotide variants and copy number variants. In healthy individuals, we can observe monogenic highly penetrant variants, which may be causally responsible for diseases, and also susceptibility variants, associated with common polygenic diseases. But there is the major problem of penetrance. Thus, there is the question of whether it is worthwhile to perform WGS in all healthy individuals as a step towards Precision Medicine. The genetic architecture of disease is consistent with the fact that they are all polygenic. Moreover, ancestry adds another layer of complexity. We are now capable of obtaining Polygenic Risk Scores for all complex diseases using only data from new generation sequencing. Yet, review of available evidence does not at present favor the idea that WGS analyses are sufficiently developed to allow reliable predictions of the risk components for monogenic and polygenic hereditary diseases in healthy individuals. Probably, it is still better for WGS to remain reserved for the diagnosis of pathogenic variants of Mendelian diseases.
PubMed: 36218382
DOI: 10.1590/1678-4685-GMB-2022-0150 -
HGG Advances Oct 2023Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at...
Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPVs) in two IMD genes: , associated with Fabry disease, and , associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in or . We identified three individuals (2 male, 1 female) with PLPVs in , all of whom were undiagnosed, and three individuals (3 female) with PLPVs in , two of whom were undiagnosed. All three individuals with PLPVs in (100%) had symptoms suggestive of mild Fabry disease, and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPVs in had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. Our findings suggest that and variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care.
Topics: Female; Male; Humans; Fabry Disease; Phenotype; Genotype; Penetrance; Hospitals
PubMed: 37593415
DOI: 10.1016/j.xhgg.2023.100226 -
Human Genetics Jun 2020Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are... (Review)
Review
Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand that absent or partial clinical disease is often noted in individuals harboring disease-causing genotypes. Despite the frequency of incomplete penetrance in PID, no conceptual framework exists to categorize and explain these occurrences. Here, by reviewing decades of reports on incomplete penetrance in PID we identify four recurrent themes of incomplete penetrance, namely genotype quality, (epi)genetic modification, environmental influence, and mosaicism. For each of these principles, we review what is known, underscore what remains unknown, and propose future experimental approaches to fill the gaps in our understanding. Although the content herein relates specifically to inborn errors of immunity, the concepts are generalizable across genetic diseases.
Topics: Epigenesis, Genetic; Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Humans; Mosaicism; Penetrance; Primary Immunodeficiency Diseases
PubMed: 32067110
DOI: 10.1007/s00439-020-02131-9 -
American Journal of Neurodegenerative... 2023Parkinson's disease may be caused by a single highly deleterious and penetrant pathogenic variant in 5-10% of cases (monogenic). Research into these mutational disorders... (Review)
Review
Parkinson's disease may be caused by a single highly deleterious and penetrant pathogenic variant in 5-10% of cases (monogenic). Research into these mutational disorders yields important pathophysiological insights. This article examines the phenotype, genotype, pathophysiology, and geographic and ethnic distribution of genetic forms of disease. Well established Parkinson's disease (PD) causal variants can follow an autosomal dominant ( and ) and autosomal recessive pattern of inheritance ( and ). Parkinson's disease is a worldwide condition, yet the AfrAbia population is understudied in this regard. No prevalence or incidence investigations have been conducted yet. Few studies on genetic risk factors for PD in AfrAbia communities have been reported which supported the notion that the prevalence and incidence rates of PD in AfrAbia are generally lower than those reported for European and North American populations. There have been only a handful of documented genetic studies of PD in AfrAbia and very limited cohort and case-control research studies on PD have been documented. In this article, we provide a summary of prior conducted research on monogenic PD in Africa and highlight data gaps and promising new research directions. We emphasize that monogenic Parkinson's disease is influenced by distinctions in ethnicity and geography, thereby reinforcing the need for global initiatives to aggregate large numbers of patients and identify novel candidate genes. The current article increases our knowledge of the genetics of Parkinson's disease (PD) and helps to further our knowledge on the genetic factors that contribute to PD, such as the lower penetrance and varying clinical expressivity of known genetic variants, particularly in AfrAbian PD patients.
PubMed: 37736165
DOI: No ID Found