Family environment and polygenic risk in the bipolar high-risk context.

Background: The interaction of polygenic risk (PRS) and environmental effects on development of bipolar disorder (BD) is understudied, as are high-risk offspring perceptions of their family environment (FE). We tested the association of offspring-perceived FE in interaction with BD-PRS on liability for BD in offspring at high or low familial risk for BD. Methods: Offspring of a parent with BD (oBD; n = 266) or no psychiatric disorders (n = 174), aged 12-21 at recruitment, participated in the US and Australia. Empirically-derived profiles of FE classified offspring by their perceived levels of familial cohesion, flexibility, and conflict. Offspring BD-PRS were derived from Psychiatric Genomics Consortium BD-GWAS. Lifetime DSM-IV bipolar disorders were derived from the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. We used a novel stepwise approach for latent class modeling with predictors and distal outcomes. Results: Fifty-two offspring were diagnosed with BD. For those with well-functioning FE (two-thirds of the sample), higher BD-PRS tracked positively with liability for BD. However, for those with high-conflict FEs, the relationship between BD-PRS and liability to BD was negative, with highest risk for BD observed with lower BD-PRS. In exploratory analyses, European-ancestry offspring with BD had elevated history of suicidal ideation in high-conflict FE compared to well-functioning-FE, and of suicide attempt with low-BD-PRS and high-conflict FE. Conclusions: The data suggest that the relationship of BD-PRS and offspring liability for BD differed between well-functioning versus high-conflict FE, potentially in line with a multifactorial liability threshold model and supporting future study of and interventions improving family dynamics.

Ethical, legal, and social implications of genetic risk prediction for multifactorial disease: a narrative review identifying concerns about interpretation and use of polygenic scores.

Advances in genomics have enabled the development of polygenic scores (PGS), sometimes called polygenic risk scores, in the context of multifactorial diseases and disorders such as cancer, cardiovascular disease, and schizophrenia. PGS estimate an individual's genetic predisposition, as compared to other members of a population, for conditions which are influenced by both genetic and environmental factors. There is significant interest in using genetic risk prediction afforded through PGS in public health, clinical care, and research settings, yet many acknowledge the need to thoughtfully consider and address ethical, legal, and social implications (ELSI). To contribute to this effort, this paper reports on a narrative review of the literature, with the aim of identifying and categorizing ELSI relating to genetic risk prediction in the context of multifactorial disease, which have been raised by scholars in the field. Ninety-two articles, spanning from 1977 to 2021, met the inclusion criteria for this study. Identified ELSI included potential benefits, challenges and risks that focused on concerns about interpretation and use, and ethical obligations to maximize benefits, minimize risks, promote justice, and support autonomy. This research will support geneticists, clinicians, genetic counselors, patients, patient advocates, and policymakers in recognizing and addressing ethical concerns associated with PGS; it will also guide future empirical and normative research.

Agregación familiar para cardiopatía isquémica

RESUMEN Fundamento: la cardiopatía isquémica es una entidad nosológica de origen multifactorial con predisposición genética y susceptible a cambios ambientales. Objetivo: determinar la existencia de agregación familiar para cardiopatía isquémica en pacientes atendidos en consulta de cardiología en el Hospital General Docente Vladimir Ilich Lenin de Holguín. Métodos: se realizó un estudio observacional, analítico de casos y controles (estudio de agregación familiar). La muestra quedó conformada por 60 nuevos pacientes con el diagnóstico de cardiopatía isquémica (casos) y por otros 60 pacientes sin diagnóstico de enfermedad coronaria (controles), pareadas en la razón 1:1. Se emplearon como variables: sexo, edad, antecedentes familiares de cardiopatía isquémica y factores de riesgo ambientales. Se utilizó el estadígrafo Chi cuadrado. Luego se calculó el Odds Ratio para conocer la magnitud de asociación mediante la razón de productos cruzados. Resultados: en el grupo casos existió una mayor frecuencia en el antecedente familiar para cardiopatía isquémica, fue más elevada para los familiares de primer grado con 31 familiares y un 41,3 %. La hiperlipidemia se presentó como el factor de riesgo de mayor frecuencia con 36,7 % en el grupo casos y 37,1 % en el grupo controles. Se determinó un riesgo aproximadamente 4 veces mayor de padecer cardiopatía isquémica en aquellos individuos con historia familiar positiva de primer grado, mientras que los pacientes con hiperlipidemia tienen 4,8 más riesgo de padecer cardiopatía isquémica. Conclusiones: existe agregación familiar para cardiopatía isquémica y se mostró un riesgo mayor de enfermar los pacientes con historia familiar positiva para la enfermedad, principalmente con familiares de primer grado y con hiperlipidemia.

ABSTRACT Background: ischemic heart disease is a nosological entity of multifactorial origin with genetic predisposition and susceptible to environmental changes. Objective: to determine the existence of familial aggregation for ischemic heart disease in patients seen in the cardiology clinic at the Vladimir Ilich Lenin General Teaching Hospital in Holguín. Methods: an analytical observational study of cases and controls (family aggregation study) was carried out. The sample was made up of 60 new patients with a diagnosis of ischemic heart disease (cases) and another 60 patients without a diagnosis of coronary heart disease (controls), paired in a 1:1 ratio. The following variables were used: sex, age, family history of ischemic heart disease and environmental risk factors: smoking, hyperlipidemia, high blood pressure and sedentary lifestyle. The Chi square statistician was used by the Mantel-Haenszel method. The odds ratio (OR) was then calculated to determine the magnitude of association through the ratio of cross products. Results: in the case group there was a higher frequency in the family history for ischemic heart disease, being higher for first degree relatives with 31 relatives and 41.3 %. Hyperlipidemia was the most frequent risk factor with 36.7 % in the case group and 37.1 % in the control group. An approximately 4-fold increased risk of suffering from ischemic heart disease was determined in those individuals with a positive first-degree family history, while patients with hyperlipidemia have a 4.8 times greater risk of suffering from ischemic heart disease. Conclusions: there is family aggregation for ischemic heart disease and a higher risk of getting sick was shown in patients with a positive family history for the disease, mainly with first-degree relatives and with hyperlipidemia.

Cancer Risk Score Prediction Based on a Single-Nucleotide Polymorphism Network.

OBJECTIVES: Genome-wide association studies (GWAS) are performed to study the associations between genetic variants with respect to certain phenotypic traits such as cancer. However, the method that is commonly used in GWAS assumes that certain traits are solely affected by a single mutation. We propose a network analysis method, in which we generate association networks of single-nucleotide polymorphisms (SNPs) that can differentiate case and control groups. We hypothesize that certain phenotypic traits are attributable to mutations in groups of associated SNPs. METHODS: We propose a method based on a network analysis framework to study SNP-SNP interactions related to cancer incidence. We employed logistic regression to measure the significance of all SNP pairs from GWAS for the incidence of colorectal cancer and computed a cancer risk score based on the generated SNP networks. RESULTS: We demonstrated our method in a dataset from a case-control study of colorectal cancer in the South Sulawesi population. From the GWAS results, 20,094 pairs of 200 SNPs were created. We obtained one cluster containing four pairs of five SNPs that passed the filtering threshold based on their p-values. A locus on chromosome 12 (12:54410007) was found to be strongly connected to the four variants on chromosome 1. A polygenic risk score was computed from the five SNPs, and a significant difference in colorectal cancer risk was obtained between the case and control groups. CONCLUSIONS: Our results demonstrate the applicability of our method to understand SNP-SNP interactions and compute risk scores for various types of cancer.

Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Cardiovascular disease is the leading contributor to years lost due to disability or premature death among adults. Current efforts focus on risk prediction and risk factor mitigation' which have been recognized for the past half-century. However, despite advances, risk prediction remains imprecise with persistently high rates of incident cardiovascular disease. Genetic characterization has been proposed as an approach to enable earlier and potentially tailored prevention. Rare mendelian pathogenic variants predisposing to cardiometabolic conditions have long been known to contribute to disease risk in some families. However, twin and familial aggregation studies imply that diverse cardiovascular conditions are heritable in the general population. Significant technological and methodological advances since the Human Genome Project are facilitating population-based comprehensive genetic profiling at decreasing costs. Genome-wide association studies from such endeavors continue to elucidate causal mechanisms for cardiovascular diseases. Systematic cataloging for cardiovascular risk alleles also enabled the development of polygenic risk scores. Genetic profiling is becoming widespread in large-scale research, including in health care-associated biobanks, randomized controlled trials, and direct-to-consumer profiling in tens of millions of people. Thus, individuals and their physicians are increasingly presented with polygenic risk scores for cardiovascular conditions in clinical encounters. In this scientific statement, we review the contemporary science, clinical considerations, and future challenges for polygenic risk scores for cardiovascular diseases. We selected 5 cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) and response to drug therapy and offer provisional guidance to health care professionals, researchers, policymakers, and patients.

Prediction of clinically significant prostate cancer using polygenic risk models in Asians.

PURPOSE: To develop and evaluate the performance of a polygenic risk score (PRS) constructed in a Korean male population to predict clinically significant prostate cancer (csPCa). MATERIALS AND METHODS: Total 2,702 PCa samples and 7,485 controls were used to discover csPCa susceptible single nucleotide polymorphisms (SNPs). Males with biopsy-proven or post-radical prostatectomy Gleason score 7 or higher were included for analysis. After genotype imputation for quality control, logistic regression models were applied to test association and calculate effect size. Extracted candidate SNPs were further tested to compare predictive performance according to number of SNPs included in the PRS. The best-fit model was validated in an independent cohort of 311 cases and 822 controls. RESULTS: Of the 83 candidate SNPs with significant PCa association reported in previous literature, rs72725879 located in PRNCR1 showed the highest significance for PCa risk (odds ratio, 0.597; 95% confidence interval [CI], 0.555-0.641; p=4.3×10-45). Thirty-two SNPs within 26 distinct loci were further selected for PRS construction. Best performance was found with the top 29 SNPs, with AUC found to be 0.700 (95% CI, 0.667-0.734). Males with very-high PRS (above the 95th percentile) had a 4.92-fold increased risk for csPCa. CONCLUSIONS: Ethnic-specific PRS was developed and validated in Korean males to predict csPCa susceptibility using the largest csPCa sample size in Asia. PRS can be a potential biomarker to predict individual risk. Future multi-ethnic trials are required to further validate our results.

Association of FTO variant with parental history of type 2 diabetes mellitus in adults.

OBJECTIVE: To find out the association between fat mass and obesity-associated gene polymorphism and risk factors frequently associated with type 2 diabetes mellitus. METHODS: The case-control study was conducted from January 2020 to March 2021 at the Ziauddin University, Karachi, and comprised deoxyribonucleic acid samples for fat mass and obesity-associated gene polymorphism from non-diabetic Pakistani population. Group A comprised non-diabetics with parental history of type 2 diabetes mellitus and Group B had controls without parental history of type 2 diabetes mellitus. Analysis was based on restriction fragment length polymorphism and polymerase chain reaction. Data was analysed using SPSS 25. RESULTS: Of the 150 subjects, 75(50%) each were in Group A and Group B. There were 40 (53.3%) males and 35 (46.7%) females in Group A compared to 35 (46.7%) males and 40(53.3%) females in Group B. Overall, 48% subjects were single and 52 % were married. A difference in frequency of fat mass and obesity-associated gene (rs9939609) alleles, such as TT, AA TA, was noted between the groups (p>0.999). TA allele was found to be associated with Group A (33) 44% (p=0.40), while TT allele was associated with Group B (41) 54% (p=0.414). AA allele was equally distributed between the groups (6) 8% (p=1.00). CONCLUSIONS: The TT allele of fat mass and obesity-associated gene was found to be an independent allele associated with the risk of developing type 2 diabetes mellitus.

Multi-omic strategies applied to the study of pharmacoresistance in mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy in adults, and hippocampal sclerosis (HS) is a frequent histopathological feature in patients with MTLE. Pharmacoresistance is present in at least one-third of patients with MTLE with HS (MTLE+HS). Several hypotheses have been proposed to explain the mechanisms of pharmacoresistance in epilepsy, including the effect of genetic and molecular factors. In recent years, the increased knowledge generated by high-throughput omic technologies has significantly improved the power of molecular genetic studies to discover new mechanisms leading to disease and response to treatment. In this review, we present and discuss the contribution of different omic modalities to understand the basic mechanisms determining pharmacoresistance in patients with MTLE+HS. We provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions of these studies to improve the understanding of pharmacoresistance in MTLE+HS. However, it is important to point out that, as with other complex traits, pharmacoresistance to anti-seizure medications is likely a multifactorial condition in which gene-gene and gene-environment interactions play an important role. Thus, studies using multidimensional approaches are more likely to unravel these intricate biological processes.

Genetic Determinants of Intraocular Pressure.

Intraocular pressure (IOP) is the cardinal and only modifiable risk factor for glaucoma, the leading cause of irreparable blindness worldwide. Twin and family studies estimate the heritability of IOP to be 40-70%, and linkage studies for IOP have identified numerous loci. Mutations in MYOC can cause markedly elevated IOP and aggressive glaucoma often requiring surgical intervention. However, the majority of the genetic basis for raised IOP and glaucoma in populations is complex, and recent large genome-wide association studies (GWASs) have identified over 100 common variants that contribute to IOP variation. In combination, these loci are predictive for primary open-angle glaucoma in independent populations, achieving an area under the receiver operating characteristic curve of 76% for high-pressure primary open-angle glaucoma; this suggests the possibility of targeted screening in the future. Additionally, GWAS findings have identified important biological pathways underlying IOP regulation, including lymphangiogenesis and lipid metabolism, providing novel targets for new therapies.

Polygenic risk score for genetic evaluation of prostate cancer risk in Asian populations: A narrative review.

Decreasing costs of genetic testing and interest in disease inheritance has changed the landscape of cancer prediction in prostate cancer (PCa), and guidelines now include genetic testing for high-risk groups. Familial and hereditary PCa comprises approximately 20% and 5% of all PCa, respectively. Multifaceted disorders like PCa are caused by a combinatory effect of rare genes of high penetrance and smaller genetic variants of relatively lower effect size. Polygenic risk score (PRS) is a novel tool utilizing PCa-associated single nucleotide polymorphisms (SNPs) identified from genome-wide association study (GWAS) to generate an additive estimate of an individual's lifetime genetic risk for cancer. However, most PRS are developed based on GWAS collected from mainly European populations and do not address ethnic differences in PCa genetics. This review highlights the attempts to generate a PRS tailored to Asian males including data from Korea, China, and Japan, and discuss the clinical implications for prediction of early onset and aggressive PCa.

Multi-omics in mesial temporal lobe epilepsy with hippocampal sclerosis: Clues into the underlying mechanisms leading to disease.

Mesial temporal lobe epilepsy (MTLE) is one of the most common types of focal epilepsy in the adult population. MTLE is frequently associated with a specific histopathological lesion in the medial temporal structures, namely hippocampal sclerosis (HS). A significant proportion of patients with MTLE+HS have severe epilepsy, which is often resistant to clinical treatment. For these patients, surgical resection of the epileptogenic lesion can be performed. Our understanding of the underlying mechanisms leading to MTLE+HS has improved significantly over the past few decades. In this review, we aim to present and discuss the most recent findings regarding the genetic determinants of MTLE+HS. Furthermore, we will address studies about transcriptomics, proteomics, metabolomics, and epigenomic signatures of the tissue that is surgically removed from patients with refractory MTLE+HS and animal models of the disorder. We expect to provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions for multi-omics studies in MTLE+HS.

Genetic approaches toward understanding the individual variation in cardiac structure, function and responses to exercise training.

Cardiovascular disease (CVD) accounts for approximately 30% of all deaths worldwide and its prevalence is constantly increasing despite advancements in medical treatments. Cardiac remodeling and dysfunction are independent risk factors for CVD. Recent studies have demonstrated that cardiac structure and function are genetically influenced, suggesting that understanding the genetic basis for cardiac structure and function could provide new insights into developing novel therapeutic targets for CVD. Regular exercise has long been considered a robust nontherapeutic method of treating or preventing CVD. However, recent studies also indicate that there is inter-individual variation in response to exercise. Nevertheless, the genetic basis for cardiac structure and function as well as their responses to exercise training have yet to be fully elucidated. Therefore, this review summarizes accumulated evidence supporting the genetic contribution to these traits, including findings from population-based studies and unbiased large genomic-scale studies in humans.

Agregación familiar en individuos con hipertensión arterial esencial y factores de riesgo / Family Aggregation in Individuals with Essential Arterial Hypertension and Risk Factors

RESUMEN Fundamento: la hipertensión arterial es la elevación constante de las cifras de tensión arterial con un origen poligénico y mutifactorial. Es la hipertensión arterial una enfermedad de alta incidencia y prevalencia a nivel mundial. Objetivo: demostrar la agregación familiar para hipertensión arterial esencial y factores de riesgo en individuos afectados. Método: se realizó una investigación observacional, analítica, longitudinal y retrospectiva, de caso/ control a partir de la consulta de referencia para enfermedades crónicas no transmisibles en Banes, provincia Holguín durante el período octubre 2019 marzo 2020. El universo abarcó la totalidad de individuos diagnosticados y sus familias. Por muestreo aleatorio simple, se obtuvo la muestra de 91 casos. Se conformó el grupo control a razón de 3:1 que incluyó 273 individuos. Fueron cumplidos los requisitos bioéticos. Se aplicaron criterios de inclusión/exclusión. Fueron utilizados los estadígrafos: Chi cuadrado, Odd Ratio (OR), incluidos p e intervalo de confianza. Se operacionalizaron las variables: edad, sexo, grado de consanguinidad y factores de riesgo. Se obtuvo el árbol genealógico. Resultados: los grupos de edades 56-65 años y 66 años y más, resultaron los más afectados. Predominó el sexo masculino (53,9 %). Los familiares de primer y segundo grado de consanguinidad mostraron la mayor incidencia de la enfermedad. Se encontró asociación entre la enfermedad y el antecedente familiar de esta (X2=321,4), con un riesgo incrementado para los familiares de los casos respecto a los controles (OR=10,93). Los factores de riesgo predominantes fueron: tabaquismo (OR=2,18) y el antecedente familiar de enfermedad (OR=0,74). Se demostró la asociación de factores de riesgo con la enfermedad (X2=176,9). Conclusiones: la hipertensión arterial esencial es una enfermedad multifactorial, compleja y poligénica con agregación familiar demostrada.

ABSTRACT Background: arterial hypertension is the constant elevation of blood pressure figures with a polygenic and multifactorial origin. Hypertension is a disease of high incidence and prevalence worldwide. Objective: to demonstrate the familial aggregation for essential arterial hypertension and risk factors in affected individuals. Method: an observational, analytical, longitudinal and retrospective case / control investigation was carried out from the reference consultation for chronic non-communicable diseases in Banes, Holguín province during the period from October 2019 to March 2020. The universe covered all individuals diagnosed and their families. By simple random sampling, the sample of 91 cases was obtained. The control group was formed at a ratio of 3:1 which included 273 individuals. Bioethical requirements were met. Inclusion / exclusion criteria were applied. The following statistics were used: Chi square, Odd Ratio (OR), including p and confidence interval. The variables were operationalized: age, sex, degree of consanguinity, and risk factors. The genealogical tree was obtained. Results: the age groups 56-65 years and 66 years and over, were the most affected. The male sex predominated (53.9 %). First and second-degree relatives of consanguinity showed the highest incidence of the disease. An association was found between the disease and its family history (X2 = 321.4) with an increased risk for relatives of the cases compared to the controls (OR = 10.93). The predominant risk factors were: smoking (OR = 2.18) and family history of disease (OR = 0.74). The association of risk factors with the disease was demonstrated (X2 = 176.9). Conclusions: essential arterial hypertension is a multifactorial, complex and polygenic disease with demonstrated familial aggregation.

Genetic mechanisms of neurodevelopmental disorders.

Neurodevelopmental disorders encompass a broad range of conditions, which include autism, epilepsy, and intellectual disability. These disorders are relatively common and have associated clinical and genetic heterogeneity. Technology has driven much of our understanding of these diseases and their genetic underlying mechanisms, particularly highlighted by the study of large cohorts with comparative genomic hybridization and the more recent implementation of next-generation sequencing (NGS). The mapping of copy number variants throughout the genome has highlighted the recurrent, highly penetrant, de novo variation in syndromic forms of neurodevelopmental disease. NGS of affected individuals and their parents led to a dramatic shift in our understanding as these studies showed that a significant proportion of affected individuals carry rare, de novo variants within single genes that explain their disease presentation. Deep sequencing studies further implicate mosaicism as another mechanism of disease. However, it has also become clear that while rare variants explain a significant proportion of sporadic neurodevelopmental disease, rare variation still does not fully account for the familial clustering and high heritability observed. Common variants, including those within these known disease genes, are also shown to contribute significantly to overall risk. There is also increasing awareness of the important contribution of epigenetic factors and gene-environment interactions.

Imaging Alzheimer's genetic risk using diffusion MRI: A systematic review.

Diffusion magnetic resonance imaging (dMRI) is an imaging technique which probes the random motion of water molecules in tissues and has been widely applied to investigate changes in white matter microstructure in Alzheimer's Disease. This paper aims to systematically review studies that examined the effect of Alzheimer's risk genes on white matter microstructure. We assimilated findings from 37 studies and reviewed their diffusion pre-processing and analysis methods. Most studies estimate the diffusion tensor (DT) and compare derived quantitative measures such as fractional anisotropy and mean diffusivity between groups. Those with increased AD genetic risk are associated with reduced anisotropy and increased diffusivity across the brain, most notably the temporal and frontal lobes, cingulum and corpus callosum. Structural abnormalities are most evident amongst those with established Alzheimer's Disease. Recent studies employ signal representations and analysis frameworks beyond DT MRI but show that dMRI overall lacks specificity to disease pathology. However, as the field advances, these techniques may prove useful in pre-symptomatic diagnosis or staging of Alzheimer's disease.

Agregación familiar y factores de riesgo de cáncer de mama en individuos afectados / Family Aggregation and Risk Factors for Breast Cancer in Affected Individuals

RESUMEN Fundamento el cáncer de mama es una enfermedad sistémica, multifactorial, polimorfa que se desarrolla en mujeres sin antecedentes familiares de la enfermedad. La posibilidad de herencia familiar se describe en 15-20 % de los casos. Objetivo: determinar la agregación familiar para cáncer de mama y los factores de riesgo asociados a este padecimiento. Método: se realizó un estudio analítico, retrospectivo, tipo caso y control, a partir de individuos que acudieron a la consulta municipal de riesgo genético, ubicada en el Policlínico Universitario César Fornet Frutos del municipio Banes, provincia Holguín en el período julio-diciembre de 2019 con el objetivo de comprobar la existencia o no de agregación familiar del cáncer de mama. Por muestreo aleatorio simple, se obtuvo la muestra conformada por 47 casos y 141 controles. Las variables operacionalizadas fueron: antecedentes personales y familiares de enfermedad oncológica, edad, menarquia, edad a la menopausia, ingestión de píldora anticonceptiva, edad de nacimiento de primer hijo, lactancia materna, ingestión de alcohol, hábito de fumar, historia familiar. Se aplicó un cuestionario diseñado a los fines del estudio. El cálculo de Chi cuadrado y Odds Ratio permitieron estimar asociación entre variables y la magnitud de asociación. Resultados: predominó el grupo de edad de 60-69 años. Los factores de riesgo hábito de fumar (OR=4,1), la ingestión de píldora anticonceptiva (OR=3,1), y el alcohol (OR=2,8) presentaron la mayor asociación a la enfermedad. Se propuso una estrategia de asesoramiento genético a partir de los resultados. Conclusiones: la confluencia de factores genéticos y ambientales, determina la agregación familiar del cáncer de mama.

ABSTRACT Foundation: breast cancer is a systemic, multifactorial, polymorphic disease that develops in women with no family history of the disease. The possibility of family inheritance is described in 15-20 % of cases. Objective: to determine the family aggregation for breast cancer and the risk factors associated with this disease. Method: an analytical, retrospective, case-control type study was carried out, from individuals who attended the municipal genetic risk consultation located at the César Fornet Frutos University Polyclinic, Banes municipality, Holguín province in the period July-December 2019 aimed at verifying the existence or not of family aggregation of breast cancer. By simple random sampling, the sample consisting of 47 cases and 141 controls was obtained. The sample, consisting of 47 cases and 141 controls, was obtained by simple random sampling. The variables were: personal and family history of oncological disease, age, menarche, age at menopause, contraceptive pill ingestion, first child age of birth, breastfeeding, alcohol intake, smoking, family history. A questionnaire designed for the purposes of the study was applied. The Chi square calculation and Odds Ratio allowed estimating association between variables and the magnitude of association. Results: the age group of 60-69 years prevailed. The risk factors for smoking (OR = 4.1), ingestion of the contraceptive pill (OR = 3.1), and alcohol (OR = 2.8) had the highest association with the disease. A genetic counseling strategy was proposed based on the results. Conclusions: confluence of genetic and environmental factors determines family aggregation of breast cancer.

Genome-Wide Association Studies of CKD and Related Traits.

The past few years have seen major advances in genome-wide association studies (GWAS) of CKD and kidney function-related traits in several areas: increases in sample size from >100,000 to >1 million, enabling the discovery of >250 associated genetic loci that are highly reproducible; the inclusion of participants not only of European but also of non-European ancestries; and the use of advanced computational methods to integrate additional genomic and other unbiased, high-dimensional data to characterize the underlying genetic architecture and prioritize potentially causal genes and variants. Together with other large-scale biobank and genetic association studies of complex traits, these GWAS of kidney function-related traits have also provided novel insight into the relationship of kidney function to other diseases with respect to their genetic associations, genetic correlation, and directional relationships. A number of studies also included functional experiments using model organisms or cell lines to validate prioritized potentially causal genes and/or variants. In this review article, we will summarize these recent GWAS of CKD and kidney function-related traits, explain approaches for downstream characterization of associated genetic loci and the value of such computational follow-up analyses, and discuss related challenges along with potential solutions to ultimately enable improved treatment and prevention of kidney diseases through genetics.

From Polygenic Scores to Precision Medicine in Alzheimer's Disease: A Systematic Review.

BACKGROUND: Late-onset Alzheimer's disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual's risk alleles, have been used to draw inferences about the pathological processes underpinning AD. OBJECTIVE: This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration. METHODS: We searched the literature from July 2008-July 2018 following PRISMA guidelines. RESULTS: 57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes. CONCLUSION: PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity.

High polygenic burden is associated with blood DNA methylation changes in individuals with suicidal behavior.

Suicidal behavior is result of the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide). Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. We identified 153 differentially methylated sites between individuals with low and high-PRS. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment (CHD7, RFX4, KCNA1, PLCB1, PITX1, NUMBL) and ATP binding (KIF7, NUBP2, KIF6, ATP8B1, ATP11A, CLCN7, MYLK, MAP2K5). Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

Association of the JAZF1 Variant in Adults With a Parental History of Type 2 Diabetes Mellitus In Pakistan.

Background Type 2 diabetes mellitus (T2DM) is a chronic multifactorial condition and quickly growing disease in Pakistan. Many genes together with Zinc finger protein 1 (JAZF1) have already been described earlier in the literature but the role of JAZF1 in this subset of the population is yet to define. This study was aimed at identifying JAZF1 polymorphism and the risk of developing T2DM in persons with a parental history of T2DM in the Pakistani population. Methods DNA samples from 75 non-diabetic Pakistani participants with a family history of T2DM and 75 controls were evaluated by using a polymerase chain reaction (PCR) and the restriction fragment length polymorphism method. Results The alleles AA and AG and the GG genotype of JAZF1 (rs864745) varied considerably in frequency distribution between cases and control (p<0.05). The GG was independently and significantly associated with cases who had a family history of T2DM [odds ratio (OR) 2.6 (95% confidence interval (Cl) 1.3-5.1); p=0.005] while the AA allele was significantly associated with controls without a family history of T2DM [odds ratio (OR) 0.39 (95% confidence interval (Cl) 0.2-0.7); p=0.0059] and the allele AG has no significance and was equally distributed among control and cases with p-value=1.000. Conclusion Genotype GG of the JAZF1 variant was found significantly associated with the risk of developing type 2 diabetes mellitus in the Pakistani subset of the population.