The bone-brain axis has emerged as a critical framework linking skeletal metabolism to neurodegeneration. Within this axis, bone marrow adipose tissue (BMAT) represents a unique fat depot with distinct endocrine and hematopoietic functions, yet its contribution to Alzheimer's disease (AD) remains unclear. We conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics to assess the causal effects of six fat depots-abdominalsubcutaneous, visceral, spinal, femoral head, total hip, and femoral diaphysis fat-on AD risk. Mediation analysis was further performed to evaluate whether femoral neck bone mineral density (BMD) mediates these associations. Among the six depots, only total hip BMAT showed a significant causal association with AD risk (OR = 1.28, 95% CI: 1.09-1.51, p = 0.003). Total hip BMAT was inversely related to femoral neck BMD (β = -0.43, 95% CI: -0.61 to -0.24, p < 0.001), whereas no causal relationship was detected between BMD and AD (OR = 1.01, 95% CI: 0.89-1.15, p = 0.849), excluding bone loss as a mediator. This study provides the first genetic evidence that excessive hip BMAT increases the risk of AD, supporting the bone-brain axis hypothesis. These findings highlight BMAT as a novel target for understanding and potentially preventing AD.

Inborn errors of immunity (IEI) refer to a heterogeneous group of monogenic disorders caused by germline variants that disrupt immune function. Among these conditions, immunodeficiency 92 (IMD92), an extremely rare autosomal recessive disorder due to c Rel deficiency that results from pathogenic variants of the REL gene. c Rel is a key actor of the NF-κB pathway with major implications in the immune response. Up untill now, only two patients with confirmed pathogenic REL variants have been reported. Here, a third case is described of a 5-year-old Moroccan child with combined immunodeficiency presenting with chronic diarrhea and recurrent opportunistic infections, alongside newly reported features including craniosynostosis, language delay, and epilepsy. Clinical exome sequencing, confirmed by Sanger sequencing, identified a novel homozygous frameshift variant (NM_001291746.4) REL:c.24del p.(Tyr9Ilefs*2). This variant introduces a very early premature stop codon. Western blot analysis of peripheral blood mononuclear cells demonstrated a severe reduction of c Rel protein expression with preserved p65 levels, confirming its functional impact. This report expands the mutational spectrum of REL and further supports the critical, non-redundant role of c-Rel in human immune homeostasis. It also highlights the central role of next generation sequencing, particularly clinical exome approaches, in the diagnosis and evolving genetic classification of IEI, enabling earlier recognition, refined subclassification, and more personalized management of affected patients.

With the increasing prevalence of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy (EP) worldwide, there is a growing burden on medical and healthcare resources. Therefore, it is crucial to identify the etiology of these diseases and implement targeted preventive, diagnostic, and treatment measures to address the existing shortage of medical resources. Lipids are integral components of biological membranes. They not only function in energy storage and maintaining cell structure but also play a pivotal role in intercellular communication and signal transmission. Hence, lipids may hold significant implications in the pathogenesis and progression of the aforementioned disorders. Utilizing two-sample Mendelian randomization (MR) in this investigation, the IEU OpenGWAS database was analyzed to explore the potential causal association between 159 lipids and the mentioned conditions, with sensitivity analysis being performed. Differentially expressed genes (DEGs) were obtained through data analysis of these three diseases in the GEO database, followed by enrichment analysis and protein-protein interaction (PPI) network analysis. The findings indicated a potential causal association between the onset and progression of these disorders and 20 lipids categorized into six groups, which include sterol esters (SEs), ceramides (Cer), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and triacylglycerol (TAG). Furthermore, these lipids were found to regulate biological processes and pathways associated with endocytosis, synaptic vesicular circulation, signal release, MAPK signaling pathway, PI3 kinase (PI3K)-AKT signaling pathway, dopaminergic synapses, and malaria infection. It is worth noting that based on the comprehensive scores of protein interactions in the STRING database, as well as their connectivity and association strength with other proteins in the network, heat shock factor binding protein 1 (HSPB1), which is closely related to lipids and has a relatively close relationship with diseases, was identified as a key protein for AD. Similarly, RAB3A was identified as a key protein for PD. CD160 serves as the key protein of EP. This study, by combining MR with bioinformatics analysis, discovered the potential lipid-based biological processes, pathways, and biomarkers of AD, PD, and EP, respectively, suggesting new therapeutic targets for us, deepening our understanding of the mechanisms of neurological diseases, and providing support for future clinical interventions.

Dyslipidemia is a heterogeneous group of disorders that typically presents asymptomatically during childhood but increases the risk of atherosclerotic cardiovascular disease later in life. Understanding the genetic basis can provide valuable insights for early diagnosis and may support more tailored therapeutic approaches. This study aimed to investigate the genetic etiology of childhood-onset dyslipidemia and explore genotype-phenotype correlations. We retrospectively analyzed genetic data from 133 pediatric patients evaluated for suspected dyslipidemia between 2018 and 2023. Targeted next-generation sequencing (NGS) was performed using a panel covering 20 genes associated with lipid metabolism. Only pathogenic or likely pathogenic variants were included in the analysis. Pathogenic or likely pathogenic variants were identified in 17% of patients (n = 23). The most frequently affected gene was LDLR (74%), followed by significant variants in APOB, APOA5, LDLRAP1, and ALMS1. Three novel pathogenic variants were identified in this cohort: a splice-site variant in LDLRAP1 (c.231+2T>C) and two truncating variants in APOB (p.Tyr992Ter and p.Lys576Ter). Genotype-phenotype analysis revealed distinct impacts of variant types on lipid profiles. Notably, APOB variants were associated with both hypercholesterolemia and hypocholesterolemia. Our findings highlight the substantial contribution of genetic factors to childhood dyslipidemia and underscore the clinical utility of genetic testing in guiding diagnostic and therapeutic decisions.

Mitochondrial proteins are encoded by both mitochondrial- and nuclear-encoded genes. Because mitochondrial DNA (mtDNA) is maternally inherited, admixed individuals may have different ancestral sources for their nuclear and mitochondrial genomes. The potential incompatibility between these genomic components may cause suboptimal mitochondrial function and result in energy-related pathologies. This incompatibility, or 'mitonuclear discordance', is defined as the proportion of the nuclear genome not derived from the same ancestral source as the mtDNA. Based on this understanding, we hypothesized that increased mitonuclear discordance would be associated with lower mitochondrial copy number and increased risk of gout, type 2 diabetes and chronic kidney disease. We tested this prediction using genomic data from a cohort of 2301 New Zealanders with Polynesian ancestry (Indigenous Māori and Pacific peoples living in Aotearoa New Zealand). We observed that increased mitonuclear discordance was correlated with a decreased chance of gout (p = 5.08×10-5) and a decreased chance of diagnosis with type 2 diabetes, specifically in individuals having haplogroup B4a1a (p = 4.20×10-9), which was present in 86.0% of the Polynesian study cohort. No significant association was found between mitonuclear discordance and mitochondrial copy number (p = 0.93), risk of chronic kidney disease (p = 0.084) or gout flare frequency (p = 0.53). Overall, while these results contradicted our hypothesis, they can potentially be explained by a higher prevalence of disease-associated alleles for gout and type 2 diabetes in Polynesian genomes.

Neurological disorders affect both the central and peripheral nervous systems, exhibiting broad genetic and clinical variability and posing a significant public health concern. These conditions range from common disorders, such as attention deficit disorder and epilepsy, to rare diseases like intellectual disability (ID) and white matter disorders. Exome sequencing (ES) has emerged as a powerful tool in diagnosing the genetic underpinnings of these disorders. ES demonstrated its feasibility as a cost-effective diagnostic pathway by identifying pertinent diagnostic outcomes in 29.4% of cases and being noticeably more cost-effective than conventional genetic diagnostic techniques. This study investigated the genetic basis of three rare neurological disorders in three unrelated Pakistani families using ES. Each family presents with a distinct syndromic form of ID, associated with bilateral frontoparietal polymicrogyria (BFPP) (Family-1), Li-Ghorbani-Weisz-Hubshman syndrome (LIGOWS) (Family-2), or hypomyelination and congenital cataract (HCC) (Family-3). The functional consequences of the missense variants were investigated using bioinformatic prediction tools to confirm the pathogenicity. In Family-1 with BFPP, ES identified a novel homozygous missense variant ((NM_001145771.3): c.1579C>T; (NP_001139243.1): p.Pro527Ser) in ADGRG1, predicted to impact protein function. In Family-2 with LIGOWS, a novel homozygous missense variant ((NM_182958.4): c.649A>C; (NP_892003.2): p.Met217Leu) was found in KAT8. In Family-3 with HCC, a novel homozygous nonsense variant ((NM_032581.4): c.722T>G; (NP_115970.2): p.Leu241Ter) was identified in FAM126A, likely resulting in a truncated, nonfunctional protein. Families' structures and segregation analysis confirm disease condition segregating with autosomal recessive mode of inheritance. The functional consequences of the ADGRG1 and KAT8 missense variants were revealed as deleterious using bioinformatic prediction tools. We have identified novel pathogenic variants in ADGRG1, KAT8, and FAM126A in individuals with rare neurological disorders, thereby expanding the genetic and clinical spectrum of these conditions. This study reports, for the first time, an autosomal recessive inheritance pattern for a KAT8-related disorder, providing new insights into its genetic architecture.

Atherosclerosis (AS) is a leading cause of cardiovascular disease, and current treatments often fail to induce plaque regression. This study aims to identify novel, genetically supported therapeutic targets for AS to enable more effective drug development. We employed an integrative multiomics framework, primarily using summary-data-based Mendelian randomization (SMR) to assess causal relationships between druggable genes and AS. We combined GWAS data for AS with blood cis-expression quantitative trait loci (cis-eQTL) data from three independent cohorts. Promising candidates were rigorously validated using external AS datasets, cross-tissue cis-eQTLs, two-sample MR, colocalization, and linkage disequilibrium score regression (LDSC). Further multiomics validation incorporated cis-methylation QTL (cis-mQTL) and cis-splicing QTL (cis-sQTL) data. We evaluated target safety via phenome-wide association study (PheWAS) and characterized cellular expression in atherosclerotic plaques using single-cell RNA sequencing (scRNA-seq). Finally, we predicted candidate therapeutics using the DGIdb database. SMR screening nominated PSMA4 as a top candidate, a finding consistently replicated across external cohorts and tissues. Two-sample MR confirmed a causal effect of PSMA4 on AS risk, which was supported by strong colocalization evidence (PP.H4 = 0.941). Multiomics analyses revealed that a specific methylation site and a splicing site of PSMA4 influence AS risk by regulating its expression. LDSC indicated a significant shared genetic basis. PheWAS suggested a favorable safety profile, and scRNA-seq pinpointed high PSMA4 expression in plaque immune cells like macrophages and dendritic cells. Drug prediction identified several proteasome inhibitors, including carfilzomib and bortezomib, as potential therapeutics. This study establishes PSMA4 as a promising therapeutic target for AS, with robust genetic causality and a potential path for drug repurposing.

Breast cancer (BC) is a major global health concern. Although observational studies have reported an association between hypertension and BC risk, the causal nature of this relationship remains unclear. We performed a univariate two-sample Mendelian randomization (MR) analysis to investigate the causal effect of genetically predicted hypertension on overall BC risk and its molecular subtypes. Summary-level genetic data for hypertension were obtained from the Africa Wits-INDEPTH Partnership for Genomic Research (AWI-Gen) study conducted in sub-Saharan Africa (n=10,775). Single-nucleotide polymorphisms (SNPs) for exposure and outcome were harmonized before analysis. Causal estimates were primarily derived using the inverse-variance weighted (IVW) method with random effects, complemented by MR-Egger, weighted median, weighted mode, simple mode, and MR-robust adjusted profile score (RAPS) approaches. Sensitivity analyses assessed heterogeneity and horizontal pleiotropy, and reverse MR analyses evaluated potential causal effects of overall BC on hypertension. Additionally, colocalization analyses were conducted to determine whether hypertension- and BC-associated variants share common causal signals across genomic loci. After Bonferroni correction for multiple testing (p<0.003), no statistically significant associations were observed between genetically predicted hypertension and overall BC or its molecular subtypes: overall BC (odds ratio [OR]=1.26, 95% confidence interval [CI]: 0.86-1.83, p=0.23), estrogen receptor-positive BC (OR=1.29, 95% CI: 0.81-2.06, p=0.28), estrogen receptor-negative (ER-) BC (OR=1.90, 95% CI: 1.06-3.41, p=0.03), and triple-negative BC (OR=1.98, 95% CI: 1.95-4.14, p=0.07). The nominal association observed for ER- BC did not withstand correction for multiple testing. Colocalization analyses revealed generally low posterior probabilities for shared causal variants (PP.H4<0.5) across all BC subtypes. Findings were consistent across sensitivity analyses, and reverse MR provided no evidence of causality in the opposite direction. This study represents the first MR and colocalization investigation of hypertension and BC risk in a sub-Saharan African population. Although no evidence of a direct genetic causal relationship was identified, the combined MR and colocalization findings suggest that previously reported associations may be driven by nongenetic metabolic or vascular mechanisms rather than shared inherited genetic determinants. Further studies in larger and more diverse populations are warranted to confirm these findings and explore underlying biological pathways.

Previous studies have highlighted significant genetic structure among Southeast Asian populations, with Northern Borneo natives closely related to Austronesians from Taiwan and the Philippines, and Peninsular Malaysia indigenous populations potentially linked to the indigenous Andamanese. In this study, we analyzed 96 genomes from indigenous populations in Peninsular Malaysia, genotyped with approximately 2 million genome-wide autosomal SNPs, alongside datasets from Singapore cosmopolitan Malays and five native populations from Sabah, Northern Borneo. Our findings reveal distinct genetic structures between indigenous populations and Malays, despite their shared habitat. The Malays exhibit substantial admixture with East Asian, Austronesian, and indigenous Peninsular Malaysian ancestral components. Indigenous populations showed lower within-population diversity and longer linkage disequilibrium compared to benchmark populations. Estimated divergence times suggest that the Semang represent an earlier branching population (∼10,000 years ago), followed by Northern Borneo natives (∼7,600-6,H800 years ago), with Malays diverging more recently. These results support a scenario of successive migration waves into Southeast Asia, providing insights into the genetic history and population structure of the region.