Frontiers in Genetics

STUDY QUESTION[Do structural genomic variants, that can be identified by using optical genome mapping, contribute to male infertility?] SUMMARY ANSWER[By using optical genome mapping we can identify several types of structural variants, both known and new, that may contribute to male infertility.] WHAT IS KNOWN ALREADY[Traditional approaches such as karyotyping, CFTR and chromosome Y microdeletion testing are successful in explaining clinical findings in [~]30% of MI patients, leaving the rest...

Genome wide association studies (GWAS), combined with fine-mapping have identified 196 independent signals associated with breast cancer risk. Deciphering the functional basis of these associations can inform our understanding of the biology and aetiology of breast cancer. Decoding GWAS risk associations is challenging due to linkage disequilibrium between variants and because most variants map to non-coding regions, influencing breast cancer risk via cis-regulatory mechanisms that modulate the ...

Until now, most genetic risk for vascular dementia (VD) remains unknown. Here, we firstly performed the largest cross-ancestry genome-wide association study meta-analysis comprising 5,886 VD and 1,027,883 controls of European, East Asian, South Asian, African, and Admixed American ancestry. We identified 37 genome-wide significant loci including CLU and APOE tagged by common variants and 35 loci tagged by rare variants, and demonstrated enrichment of VD heritability in lung and genetic associati...

The genetic relationship between asthma and lung function may be dependent on age-at-onset (AAO) of asthma. We investigated whether the shared genetics between asthma AAO and lung function is dependent on AAO. Asthma cases from UK Biobank were subset according to their AAO and genetic correlation was used to obtain genetically homogeneous groups, i.e., [≤]20 (LT20), 20-40, and >40 (GT40) years. Association analysis and fine-mapping were performed to identify shared genetics between AAO groups...

We assessed the impact of plasma protein quantitative trait loci (pQTL) on therapeutic hypotheses backed by human genetic evidence. We show that pQTL-supported target-indication pairs were 4.7 times more likely to advance from Phase I to launch, compared to a 2.6-fold increase observed only with human genetic evidence. Moreover, pQTL-based enrichment was prominent in druggable protein families which had limited enrichment from human genetic evidence alone.

Body mass index (BMI), type 2 diabetes (T2D) and associated cardiometabolic features modify Alzheimers disease (AD) risk, yet shared mechanisms remain poorly understood. Using sex- and age-stratified genotyping data for BMI and T2D, we investigate how these traits converge on shared genetic pathways to AD risk. Employing multi-trait, machine learning and single-cell transcriptomics, we identify sex-specific cardiometabolic liability linked to higher BMI-associated risk in women and T2D-driven ri...

Type 2 diabetes (T2D) affects 11.1% of the global population, underscoring the need for biomarkers that inform treatment response and glycemic outcomes. We evaluated the association between the FTO variant rs9939609-A and glycemic control in a Mexican population. A total of 174 individuals living with T2D from Merida and Sisal, Yucatan, were included, of whom 85% were receiving oral hypoglycemic agents as main treatment. Glycemic control was defined cross-sectionally as good ([≤]130 mg/dL, n=...

Hypothalamic-pituitary-adrenal axis (HPA axis) dysregulation is a risk factor for poor mental and physical health. Animal studies indicate that DNA methylation may be one mechanism through which stress can influence the function of the HPA axis, however human studies have not identified consistent individual loci. Machine learning can be used to develop methylation profile scores (MPSs), but this method has not yet been applied to HPA axis function. Using a novel machine learning pipeline, we de...

Trade-offs form a key constraint in many aspects of organismal evolution, though they may help maintain genetic diversity. Late-onset Alzheimers disease (LOAD) shows features in common with the male-female health survival paradox: females suffer from higher prevalence and risk, as well as faster rates of cognitive decline while males suffer higher mortality. Though antagonistic pleiotropy could explain the tendency of LOAD to appear late in life, the sexually dimorphic profile suggests a role fo...

Opioid use disorder (OUD) is characterized by compulsive drug seeking and impaired executive control arising from maladaptive plasticity within cortico-striatal circuits. While transcriptomic studies have identified coding gene alterations in the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC), the contribution of the noncoding genome remains poorly defined. Here, we performed integrative transcriptomic analysis of postmortem human NAc and DLPFC to systematically identify and ...

Somatic mutations and the tumor immune microenvironment in breast tumors are important predictors of treatment response and survival, yet data for Hispanic/Latina (H/L) women are limited. Here we analyzed whole exome sequencing data from tumor/normal pairs and RNAseq data from 748 H/L women and 388 non-Hispanic White (NHW) women. Overall, the somatic profiles in tumors from H/L women were similar to NHW women. However, somatic mutations in genome organizer CTCF were significantly more common in ...

Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes mellitus. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the present study, we conducted genome-wide gene by sleep duration meta-analyses, separately assessing interactions of short and long sleep, for fasting glucose, fasting insulin, and hemoglobin A1c ...

IntroductionAdverse drug reactions (ADRs) remain a major public health issue, and genetic factors contribute importantly to interindividual variability in drug response. Pharmacogenetic testing helps reduce ADR risk by optimizing drug selection and dosage, particularly in monogenic disorders. Material and MethodsWhole-exome sequencing of 6,739 samples from the Russian population was performed using the MGIEasy Universal DNA Library Prep Set on the DNBSEQ-G400 platform (MGI). Variants in 48 gene...

Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of pediatric kidney failure, yet the genetic etiologies remain elusive for most affected individuals. Reanalysis of trio exome sequencing data from 80 Chinese CAKUT patients identified 32 rare, predicted deleterious variants. Replication in unrelated families from a national multicenter database prioritized four novel candidate genes--DOCK11, MIB1, TENM2, and TNS1. These candidates are involved in both well-charac...

BackgroundPersonalized pharmacotherapy requires systematic consideration of genetic factors influencing drug efficacy and safety. The accumulation of large-scale whole-exome sequencing (WES) data provides an opportunity to assess population frequencies of clinically significant pharmacogenetic variants; however, the diagnostic applicability of exome data for pharmacogenomics remains insufficiently studied. Materials and MethodsA retrospective analysis of 6,102 anonymized sequencing datasets obt...

Heterozygous FOXL2 (non-)coding sequence and structural variants (SVs) lead to blepharophimosis, ptosis and epicanthus inversus syndrome (BPES), a rare, autosomal dominant developmental disorder characterized by a completely penetrant eyelid malformation and incompletely penetrant primary ovarian insufficiency (POI). We collected variants from our in-house database, generated via clinical genetic testing and downstream research testing in the Center for Medical Genetics Ghent, Belgium (2001-202...

Alzheimers disease (AD) is marked by hallmark neuropathological changes in the brain. However, its upstream genetic determinants, beyond the central nervous system (CNS), remain largely unexplored. To that extent, we integrated human genomic data with cross-tissue and single-cell analyses across up to 40 peripheral tissues and 100 brain regions. We observed limited genetic enrichment in the CNS, with brain-resident microglia emerging as the sole enriched cell type. Instead, AD risk loci were pre...

Cancer heterogeneity is traditionally attributed to multiple parallel signaling pathways. This belief is challenged here by proposing the ER/PR axis as the dominant pathway underlying the full spectrum of breast cancer. Absolutely quantitated ER, PR, Her2 and Ki67 protein levels were accumulated over 8 years from 1652 specimens collected non-selectively and measured with Quantitative Dot Blot (QDB) method over time. Cox analysis showed ER and Ki67 as independent adverse prognostic factors while ...

This study aimed to evaluate the prognostic value of quantitative analysis of {superscript 1}F-FDG positron emission tomography (PET)/computed tomography (CT) metabolic parameters in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy (NACT). A retrospective analysis was conducted on the clinical and imaging data of 44 patients with pathologically confirmed PDAC who received NACT. All patients completed standard chemotherapy regimens and underwent {superscript 1}...

Lipoedema is a chronic adipose tissue disorder mainly affecting women with excess subcutaneous fat deposition on the lower limbs, associated with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is not well studied. We conducted a genome-wide association study (GWAS) for this disorder in a clinically ascertained cohort from Spain and performed a meta-analysis with the UK lipoedema cohort GWAS. We then used the result...