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Molecular Autism Jun 2024Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in...
BACKGROUND
Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population.
METHODS
To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families).
RESULTS
We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|> 0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3-4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D on the order of 1 × 10).
LIMITATIONS
We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification.
CONCLUSIONS
This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for < 5% of the fractional change in the estimate of the phenotypic AM. Future studies are needed to evaluate if the small increase of long-range LD induced by ancestry-related AM has impact on the downstream analysis.
Topics: Humans; Autistic Disorder; Phenotype; Male; Female; Linkage Disequilibrium; Multifactorial Inheritance; Child; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Adult; Intellectual Disability
PubMed: 38877467
DOI: 10.1186/s13229-024-00605-5 -
Journal of the American Heart... Jun 2024
Topics: Humans; Female; Coronary Artery Disease; Sex Factors; Prognosis; Multifactorial Inheritance; Risk Assessment; Genetic Predisposition to Disease; Risk Factors; Male
PubMed: 38874071
DOI: 10.1161/JAHA.123.034946 -
Revue Medicale de Liege Jun 2024Despite screening programmes, numerous clinical studies and new breast imaging techniques, breast cancer incidence for women continues to rise. The arrival of predictive... (Review)
Review
Despite screening programmes, numerous clinical studies and new breast imaging techniques, breast cancer incidence for women continues to rise. The arrival of predictive and personalized medicine could clearly redefine our screening recommendations. One promising approach to improving screening would be to use tools to predict the risk of developing breast cancer, including polygenic risk scores (PRS). This approach will enable us to offer women risk-based screening by adapting the frequency, type and age of screening. This article reviews some definitions of the PRS and breast cancer screening. We also explain the risk assessment models that have been developed and the various studies underway on personalized screening.
Topics: Humans; Breast Neoplasms; Female; Early Detection of Cancer; Risk Assessment; Preventive Medicine; Multifactorial Inheritance; Genetic Predisposition to Disease; Genetic Risk Score
PubMed: 38869126
DOI: No ID Found -
Cureus Jun 2024Type 2 diabetes mellitus (T2DM) is a consequence of insulin resistance, insulin deficiency, or both. It is usually seen in adults and is a consequence of genetic...
Metformin Monotherapy With and Without Lifestyle Changes Affects Anthropometric Parameters, Blood Pressure, Blood Glucose, and Lipid Profile in Indian Patients With Newly Diagnosed Type 2 Diabetes.
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a consequence of insulin resistance, insulin deficiency, or both. It is usually seen in adults and is a consequence of genetic (polygenic inheritance), endogenous (obesity and or hormonal factors), and environmental factors (e.g., obesogenic environment, endocrine disrupting chemicals, stress, and medicines). The prevalence of T2DM has increased over the past few decades. South Asians, including Indians, are more prone to central adiposity and develop lifestyle diseases like T2DM at body mass index values lower than those considered normal for the Western population. Generally, the first line of treatment is metformin monotherapy with lifestyle changes in patients with T2DM. Most of the research conducted on this drug is on Western subjects. Since the Indian population has genetic differences in the site of deposition of adipose and is more prone to develop lifestyle diseases, the effect of metformin may be different in Indians.
METHODS
Seventy-one (34 female, non-pregnant, non-lactating) adults with newly diagnosed T2DM were recruited in this short-duration pilot study after obtaining written informed consent. Patients regularly taking any drug were excluded, as were patients with chronic comorbidities. Treatment was initiated with metformin 500 mg OD. Lifestyle changes were recommended according to the age and physical condition of the patients. Anthropometric parameters (age, weight, height, BMI, waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR)), blood pressure, glycemic status (fasting and 2 h PP glucose and HbA1c), and lipid profile of the subjects were recorded before initiating and six months after initiating metformin monotherapy with lifestyle changes.
RESULTS
Small but statistically significant improvements were observed in the WHR,WHtR, blood pressure, blood glucose, and glycated hemoglobin. Although improvement was also observed in weight and lipid profile, these changes were not statistically significant.
CONCLUSION
This study shows that metformin monotherapy with lifestyle changes is suitable for patients of Indian origin and results in improvement in the WHR, WHtR, blood pressure, plasma glucose, and glycated hemoglobin.
PubMed: 38868550
DOI: 10.7759/cureus.62131 -
Nature Communications Jun 2024Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To...
Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To produce risk estimates relevant to clinical and public health decision-making, it is important to account for varying effects due to age and sex. Here, we develop a novel framework to estimate country-, age-, and sex-specific estimates of cumulative incidence stratified by PGS for 18 high-burden diseases. We integrate PGS associations from seven studies in four countries (N = 1,197,129) with disease incidences from the Global Burden of Disease. PGS has a significant sex-specific effect for asthma, hip osteoarthritis, gout, coronary heart disease and type 2 diabetes (T2D), with all but T2D exhibiting a larger effect in men. PGS has a larger effect in younger individuals for 13 diseases, with effects decreasing linearly with age. We show for breast cancer that, relative to individuals in the bottom 20% of polygenic risk, the top 5% attain an absolute risk for screening eligibility 16.3 years earlier. Our framework increases the generalizability of results from biobank studies and the accuracy of absolute risk estimates by appropriately accounting for age- and sex-specific PGS effects. Our results highlight the potential of PGS as a screening tool which may assist in the early prevention of common diseases.
Topics: Humans; Male; Female; Multifactorial Inheritance; Incidence; Middle Aged; Genetic Predisposition to Disease; Adult; Aged; Diabetes Mellitus, Type 2; Risk Factors; Risk Assessment; Global Burden of Disease; Sex Factors; Age Factors
PubMed: 38866767
DOI: 10.1038/s41467-024-48938-2 -
Psychiatry Research Aug 2024Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into...
Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into anxiety etiology. This study used polygenic risk scores (PRS) to explore the genetic overlap between AD and HRV, and investigated whether HRV-related polymorphisms influence anxiety risk. Resting vagally-mediated HRV was measured using a wearable device in 188 European individuals (AD=101, healthy controls=87). AD PRS was tested for association with resting HRV, and HRV PRS for association with AD. We also investigated 15 significant hits from an HRV genome-wide association study (GWAS) for association with resting HRV and AD and if this association is mediated through resting HRV. The AD PRS and HRV PRS showed nominally significant associations with resting HRV and anxiety disorders, respectively. HRV GWAS variants associated with resting HRV were rs12980262 (NDUFA11), rs2680344 (HCN4), rs4262 and rs180238 (GNG11), and rs10842383 (LINC00477). Mediation analyses revealed that NDUFA11 rs12980262 A-carriers and GNG11 rs180238 and rs4262 C-carriers had higher anxiety risk through lower HRV. This study supports an anxiety-HRV genetic relationship, with HRV-related genetic variants translating to AD. This study encourages exploration of HRV genetics to understand mechanisms and identify novel treatment targets for anxiety.
Topics: Humans; Male; Female; Adult; Anxiety Disorders; Heart Rate; Multifactorial Inheritance; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Middle Aged; Young Adult; Biomarkers; Genetic Predisposition to Disease
PubMed: 38850888
DOI: 10.1016/j.psychres.2024.115982 -
BMC Oral Health Jun 2024Individuals born with cleft lip and/or palate who receive corrective surgery regularly have abnormal growth in the midface region such that they exhibit premaxillary...
BACKGROUND
Individuals born with cleft lip and/or palate who receive corrective surgery regularly have abnormal growth in the midface region such that they exhibit premaxillary hypoplasia. However, there are also genetic contributions to craniofacial morphology in the midface region, so although these individuals appear to have Class III skeletal discrepancy, their molar relationship may be Class I. Past genome-wide association studies (GWASs) on skeletal Class II and III malocclusion suggested that multiple genetic markers contribute to these phenotypes via a multifactorial inheritance model, but research has yet to examine the genetic markers associated with dental Class I malocclusion. Thus, our goal was to conduct a family based GWAS to identify genes across the genome that are associated with Class I malocclusion, as defined by molar relations, in humans with and without clefts.
METHODS
Our cohort consisted of 739 individuals from 47 Filipino families originally recruited in 2006 to investigate the genetic basis of orofacial clefts. All individuals supplied blood samples for DNA extraction and genotyping, and a 5,766 single nucleotide polymorphism (SNP) custom panel was used for the analyses. We performed a transmission disequilibrium test for participants with and without clefts to identify genetic contributors potentially involved with Class I malocclusion.
RESULTS
In the total cohort, 13 SNPs had associations that reached the genomic control threshold (p < 0.005), while five SNPs were associated with Class I in the cohort of participants without clefts, including four associations that were identified in the total cohort. The associations for the SNPs ABCA4 rs952499, SOX1-OT rs726455, and RORA rs877228 are of particular interest, as past research found associations between these genes and various craniofacial phenotypes, including cleft lip and/or palate.
CONCLUSIONS
These findings support the multifactorial inheritance model for dental Class I malocclusion and suggest a common genetic basis for different aspects of craniofacial development.
Topics: Humans; Cleft Lip; Cleft Palate; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Female; Male; Malocclusion, Angle Class I; Cohort Studies; Linkage Disequilibrium; Child; Genotype; Adolescent; Genetic Markers; Adult; Phenotype; Multifactorial Inheritance; Young Adult
PubMed: 38849772
DOI: 10.1186/s12903-024-04444-x -
Nature Communications Jun 2024Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods...
Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk. We designed a general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. This model is designed to handle longitudinal data over the lifetime to address this unmet need and support clinical decision-making. We analyze longitudinal data from 480,638 UK Biobank participants and compared predicted lifetime risk with the 30-year Framingham risk score. MSGene improves discrimination (C-index 0.71 vs 0.66), age of high-risk detection (C-index 0.73 vs 0.52), and overall prediction (RMSE 1.1% vs 10.9%), in held-out data. We also use MSGene to refine estimates of lifetime absolute risk reduction from statin initiation. Our findings underscore our multistate model's potential public health value for accurate lifetime CAD risk estimation using clinical factors and increasingly available genetics toward earlier more effective prevention.
Topics: Humans; Coronary Artery Disease; Male; Female; Middle Aged; Electronic Health Records; Aged; Risk Assessment; Risk Factors; Adult; Genetic Predisposition to Disease; Hydroxymethylglutaryl-CoA Reductase Inhibitors; United Kingdom; Longitudinal Studies; Multifactorial Inheritance
PubMed: 38849421
DOI: 10.1038/s41467-024-49296-9 -
Scientific Reports Jun 2024Speech-in-noise (SIN) perception is a primary complaint of individuals with audiometric hearing loss. SIN performance varies drastically, even among individuals with...
Speech-in-noise (SIN) perception is a primary complaint of individuals with audiometric hearing loss. SIN performance varies drastically, even among individuals with normal hearing. The present genome-wide association study (GWAS) investigated the genetic basis of SIN deficits in individuals with self-reported normal hearing in quiet situations. GWAS was performed on 279,911 individuals from the UB Biobank cohort, with 58,847 reporting SIN deficits despite reporting normal hearing in quiet. GWAS identified 996 single nucleotide polymorphisms (SNPs), achieving significance (p < 5*10) across four genomic loci. 720 SNPs across 21 loci achieved suggestive significance (p < 10). GWAS signals were enriched in brain tissues, such as the anterior cingulate cortex, dorsolateral prefrontal cortex, entorhinal cortex, frontal cortex, hippocampus, and inferior temporal cortex. Cochlear cell types revealed no significant association with SIN deficits. SIN deficits were associated with various health traits, including neuropsychiatric, sensory, cognitive, metabolic, cardiovascular, and inflammatory conditions. A replication analysis was conducted on 242 healthy young adults. Self-reported speech perception, hearing thresholds (0.25-16 kHz), and distortion product otoacoustic emissions (1-16 kHz) were utilized for the replication analysis. 73 SNPs were replicated with a self-reported speech perception measure. 211 SNPs were replicated with at least one and 66 with at least two audiological measures. 12 SNPs near or within MAPT, GRM3, and HLA-DQA1 were replicated for all audiological measures. The present study highlighted a polygenic architecture underlying SIN deficits in individuals with self-reported normal hearing.
Topics: Humans; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Male; Female; Speech Perception; Multifactorial Inheritance; Adult; Noise; Middle Aged; Self Report; Aged; Hearing; Young Adult
PubMed: 38849415
DOI: 10.1038/s41598-024-63972-2 -
Nature Communications Jun 2024Evidence for adaptation of human skin color to regional ultraviolet radiation suggests shared and distinct genetic variants across populations. However, skin color...
Evidence for adaptation of human skin color to regional ultraviolet radiation suggests shared and distinct genetic variants across populations. However, skin color evolution and genetics in East Asians are understudied. We quantified skin color in 48,433 East Asians using image analysis and identified associated genetic variants and potential causal genes for skin color as well as their polygenic interplay with sun exposure. This genome-wide association study (GWAS) identified 12 known and 11 previously unreported loci and SNP-based heritability was 23-24%. Potential causal genes were determined through the identification of nonsynonymous variants, colocalization with gene expression in skin tissues, and expression levels in melanocytes. Genomic loci associated with pigmentation in East Asians substantially diverged from European populations, and we detected signatures of polygenic adaptation. This large GWAS for objectively quantified skin color in an East Asian population improves understanding of the genetic architecture and polygenic adaptation of skin color and prioritizes potential causal genes.
Topics: Adult; Female; Humans; Male; Middle Aged; Adaptation, Physiological; Chromosome Mapping; Genome-Wide Association Study; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Skin Pigmentation; Ultraviolet Rays; East Asian People
PubMed: 38849341
DOI: 10.1038/s41467-024-49031-4