Biomedical subjects

Richa Saxena

Publications and source records attributed to Richa Saxena.

6 recordsLinked to original sources

PubMed2026

Obesity Polygenic Risk and Healthy Lifestyle Interactions on Weight Trajectories in Women and Men.

BACKGROUND: Genetics and environmental factors contribute to obesity risk, but the extent to which healthy behaviors can offset genetic susceptibility remains unclear. We examined the interaction between obesity polygenic risk and a composite healthy lifestyle score on body mass index (BMI) trajectories in women and men. METHODS: We analyzed 13 780 women from the Nurses' Health Study and 8242 men from the Health Professionals Follow-Up Study, all of European ancestry and free of major chronic disease at baseline. The lifestyle score comprised American Heart Association Essential 8 components (nonsmoking, physical activity, healthy eating, adequate sleep) plus moderate alcohol intake, modeled as a time-varying variable. A genome-wide polygenic score for BMI was derived from genome-wide association study. Adjusted linear mixed-effects models estimated associations and interactions on biennial BMI measures over up to 26 years. RESULTS: Each SD increase in the polygenic score was associated with 1.80 kg/m2 (95% CI, 1.72-1.87) and 1.12 kg/m2 (95% CI, 1.06-1.19) higher BMI in women and men, respectively. Significant interactions between the polygenic score and healthy lifestyle score (both P<0.05) showed a dose-response attenuation of the genetic effects with healthier lifestyles. Comparing the healthiest with the least healthy lifestyle groups, genetic effects on BMI were 35% lower in women and 28% lower in men. In sensitivity analyses, higher diet quality and physical activity consistently attenuated genetic associations in both cohorts, whereas current smoking showed similar effects in women only. CONCLUSIONS: Adherence to a healthier lifestyle attenuated the association between obesity polygenic risk and BMI in a dose-response manner.

Humans↗

PubMed2026

Rare Coding Variants Reveal Distinct Genetic Architectures Across Multidimensional Sleep Phenotypes.

Sleep and circadian traits have been widely studied using common variants, but the contribution of rare coding variation remains unclear. We analyzed rare coding variants in 397,065 whole-exome sequenced UK Biobank participants across 36 sleep phenotypes from self-report, diagnoses, sleep medication use and accelerometry, and meta-analyzed results with 171,536 whole-genome sequenced All of Us participants of diverse ancestries, with replication in the Mass General Brigham Biobank (N = 31,275). We identified 260 genes associated with sleep phenotypes, including novel associations with sleep medication use in 29 genes and 24 out of 29 have not previously been reported with any sleep phenotypes. We observed modest but significant rare variant heritability and strong genetic correlations between sleep medication use, insomnia and fatigue. Temporal gene expression trajectory analyses indicate that genes associated with self-reported sleep traits show constant high prenatal expression, whereas genes linked to sleep medication phenotypes exhibit peak expression in the late prenatal period. These findings highlight distinct biological mechanisms captured by different measurement sources of sleep phenotypes and reveal rare-variant-informed targets for therapeutic discovery.

exome sequencing↗

PubMed2026

Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Humans↗

PubMed2026

Maternal and Fetal HLA Heterozygosity in Preeclampsia: Insights From a Large Multi-Ancestry Pregnancy Cohort.

Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity, with immune dysregulation at the maternal-fetal interface central to its pathogenesis. The highly polymorphic HLA region mediates maternal immune tolerance of the semi-allogeneic fetus, yet the contribution of HLA diversity to PE risk remains poorly defined. Whether the HLA heterozygote advantage observed in other immune disorders is relevant to PE has not been systematically evaluated. Using data from the multi-ancestry TOPMed Boston-Colombia Collaborative for Adverse Pregnancy Outcomes (n = 12,790; 4770 PE, 8020 controls; 10,808 maternal, 1982 fetal, including 1848 pairs), we evaluated associations between heterozygosity across eight classical HLA loci and PE and four sub-phenotypes, adjusting for genetic ancestry. HLA heterozygosity was common across most loci (> 80%). No individual maternal HLA locus was associated with overall PE; however, heterozygosity across Class I loci showed a protective effect in preterm PE (OR = 0.81, 95% CI: 0.68-0.97), with a similar pattern for HLA-A heterozygosity (OR = 0.78, 95% CI: 0.64-0.97). In contrast, fetal heterozygosity at HLA-DQB1 was nominally associated with increased risk of PE (OR = 1.36, 95% CI: 1.03-1.80) and preterm PE (OR = 1.73, 95% CI: 1.13-2.74). No individual maternal or fetal HLA alleles were associated with PE. Maternal-fetal mismatch analysis demonstrated locus-specific associations with preterm PE, including increased risk with HLA-DQA1 mismatch and reduced risk with HLA-C mismatch. These findings highlight distinct maternal and fetal immunogenetic contributions to PE risk and underscore the importance of considering HLA diversity-rather than individual alleles alone-in studies of PE aetiology.

Humans↗

PubMed2025

The genetic architecture of fibromyalgia across 2.5 million individuals.

Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here, we conduct a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts, identifying the first 26 risk loci for fibromyalgia. The strongest association was with a coding variant in HTT, the causal gene for Huntington's disease. Gene prioritization implicated the HTT regulator GPR52, as well as diverse genes with neural roles, including CAMKV, DCC, DRD2/NCAM1, MDGA2, and CELF4. Fibromyalgia heritability was exclusively enriched within brain tissues and neural cell types. Fibromyalgia showed strong, positive genetic correlation with a wide range of chronic pain, psychiatric, and somatic disorders, including genetic correlations above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome. Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females. This work provides the first robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities.

Journal Article↗

PubMed2024

Genetic and functional analysis of Raynaud's syndrome implicates loci in vasculature and immunity.

Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases. The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud's syndrome.

Raynaud Disease↗