Biomedical subjects

Qiyu Zhao

Publications and source records attributed to Qiyu Zhao.

5 recordsLinked to original sources

PubMed2026

Shared genetic architecture between major depression and intrinsic brain functional connectome organization.

BACKGROUND: Major depression (MD) is increasingly understood as a disorder characterized by widespread abnormalities in intrinsic brain functional network organization. Although both MD and brain functional connectome architecture are highly heritable, the genetic architecture underlying their relationship remains poorly characterized. METHODS: We integrated genome-wide association studies of MD with 191 ICA-based resting-state functional connectome traits to investigate their shared genetic architecture. These traits captured intrinsic connectome organization across amplitude, functional connectivity, and global connectivity domains. Cross-trait genetic analyses were used to assess pleiotropic overlap between traits. Locus-level and gene-based analyses integrating multi-omics evidence were performed to characterize the biological relevance of shared genetic signals. RESULTS: We identified significant genetic overlap between MD and 148 of 191 brain functional connectome traits. Cross-trait analyses revealed widespread shared genetic signals organized into 627 genomic loci across amplitude, functional connectivity, and global connectivity measures. Among these, 193 loci showed evidence consistent with shared causal variants based on colocalization analyses. Gene-level integration mapped these loci to 1459 protein-coding genes (390 unique genes). Multi-layer prioritization identified 17 high-confidence genes supported by convergent genomic, transcriptomic, and proteomic evidence, with enrichment in neurodevelopmental and lipid-related metabolism pathways. CONCLUSIONS: This study provides a multi-scale characterization of the shared genetic architecture between MD and intrinsic brain functional connectome organization, revealing that shared genetic signals between MD and brain functional systems are distributed across multiple functional levels and converge at the molecular level.

Connectome↗

PubMed2026

Shared genetic architecture between ADHD and intelligence varies across ADHD subtypes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition frequently accompanied by cognitive difficulties. Although previous genetic studies have demonstrated substantial overlap between ADHD and intelligence, most have treated ADHD as a single phenotype. However, whether this shared genetic architecture differs across ADHD subtypes remains unclear. METHODS: We conducted a genome-wide cross-trait analysis integrating large-scale genome-wide association study (GWAS) datasets of overall ADHD, its subtypes-childhood ADHD, persistent ADHD, and late-diagnosed ADHD-and intelligence (total N > 300,000). Genome-wide genetic correlations, polygenic overlap, local genetic correlations, and variant-level associations between ADHD phenotypes and intelligence were evaluated to characterize their shared genetic architecture. Shared variants were identified through cross-trait enrichment analyses and subsequently mapped to genes for functional annotation and gene-set enrichment. Bidirectional associations were evaluated using two-sample Mendelian randomization with sensitivity analyses. Additional GWAS datasets were used to validate the robustness of shared loci by assessing the consistency of effect directions. RESULTS: All ADHD phenotypes showed significant negative genetic correlations with intelligence (rg ranging from -0.3442 to -0.4205). Despite these modest genome-wide correlations, cross-trait analyses revealed substantial genetic overlap, including polygenic overlap, local genetic correlations, and variant-level associations. We identified 184 loci jointly associated with ADHD traits and intelligence, including 64 novel loci, whereas no shared loci were detected for persistent ADHD under the current analysis. Functional annotation revealed biologically distinct enrichment patterns across subtypes: childhood ADHD loci were linked to early neurodevelopmental processes, while late-diagnosed ADHD loci were enriched in synapse-related and neuronal signaling pathways. Mendelian randomization analyses suggested bidirectional associations, with stronger evidence supporting a directional association from intelligence to ADHD risk. Furthermore, these shared loci showed largely consistent effect directions across additional GWAS datasets, providing support for the robustness of the findings. CONCLUSIONS: The shared genetic architecture between ADHD and intelligence varies across ADHD subtypes, highlighting distinct biological pathways underlying cognitive heterogeneity in ADHD. These findings suggest that the relationship between ADHD liability and general cognitive ability is not uniform across ADHD subtypes and may inform future research on risk stratification and early identification in child and adolescent psychiatry.

Humans↗

PubMed2005

A review of the reference dose for chlorpyrifos.

Chlorpyrifos is an inhibitor of cholinesterase (ChE) and inhibition of ChE is believed to be the most sensitive effect in all animal species evaluated and in humans from previous evaluations. Recent literature, in particular epidemiology studies reporting associations between chlorpyrifos levels and fetal birth weight decreases, suggest the need to reevaluate the basis of the reference dose (RfD) for chlorpyrifos, however. In this paper, we evaluated newly available publications regarding chlorpyrifos toxicity and discuss the choice of critical effect--whether cholinesterase inhibition or developmental effect, the choice of appropriate species and study, the appropriate point of departure, and choice of uncertainty factors--including a discussion of the FQPA safety factor. We conclude that RBC cholinesterase inhibition is the critical effect, that human studies form the best choice of species--supported by a wealth of experimental animal data, that a NOAEL of 0.1 mg/kg/day is the most appropriate point of departure, and that a 10-fold factor for within human variability is sufficient to characterize the overall uncertainty in this rather large database. The resulting RfD is 0.01 mg/kg/day.

Animals↗

PubMed2005

Lower birth weight as a critical effect of chlorpyrifos: a comparison of human and animal data.

Chlorpyrifos is an irreversible inhibitor of cholinesterase (ChE), and inhibition of ChE is believed to be the most sensitive effect in all animal species evaluated and in humans. Recent epidemiology studies reported associations between umbilical cord plasma chlorpyrifos levels and fetal birth weight decreases among minority women living in New York City during pregnancy. These associations raise questions whether impaired fetal development is the critical effect rather than the inhibition of ChE as is currently believed so. We analyze the available information from epidemiology studies and animal studies in order to identify the relative sensitivity of decreased birth weight and inhibition of ChE from exposure to chlorpyrifos. We find that the positive associations from some epidemiology studies are different from other epidemiology investigations. Moreover, a direct comparison of experimental animal neonatal information shows that cholinesterase inhibition is a more sensitive indicator of adverse effect than reduced body weight, and that neonates are equally, or perhaps less sensitive to cholinesterase inhibition than their maternal parent. Based on a review of human studies and comparison of human cord blood chlorpyrifos concentrations with blood chlorpyrifos concentrations that in animals caused effects with good dose-response, it appears unlikely that the exposure level encountered by the population reported in [Whyatt, R.M., Rauh, V., Barr, D.B., Camann, D.E., Andrews, H.F., Garfinkel, R., Hoepner, L.A., Diaz, D., Dietrich, J., Reyes, A., Tang, D., Kinney, P.L., Perera, F.P., 2004. Prenatal insecticide exposures and birth weight and length among an urban minority cohort. Environ. Health Perspect. 112, 1125-1132.] study would cause any fetal developmental effect. Moreover, the critical effect for chlorpyrifos still appears to be cholinesterase inhibition.

Animals↗

PubMed2004

Reference dose for perchlorate based on thyroid hormone change in pregnant women as the critical effect.

The most relevant data for developing a reference dose (RfD) for perchlorate exposures comes from human epidemiology and clinical studies, supplemented with available and extensive information on experimental animals. Specifically, serum T4 decrease is the critical effect of perchlorate, based on a mode-of-action analysis and the evidence provided by the body of rodent studies on perchlorate. However, no T4 decreases have been observed in human populations following perchlorate exposure at non-therapeutic doses. An RfD of 0.002 mg/kg-day can be derived using an epidemiology study. A freestanding NOAEL of 0.006 mg/kg-day for T4 decrease was identified in children from the epidemiology study. The use of this NOAEL has the advantage of a being identified in a sensitive subgroup, neonates and children. Data are sufficient to estimate an overall uncertainty factor of 3-fold with this NOAEL based on expected differences in toxicokinetics and toxicodynamics between children, and pregnant women and their fetuses, the second identified sensitive subgroup for perchlorate, and concerns about the over-iodination of this population. This RfD is supported by a human clinical study using inhibition of iodine uptake in adults as a measurable surrogate for the critical effect of T4 decrease in humans. However, although this latter study has a well-established dose-response curve for inhibition of iodine uptake, even perchlorate doses that result in a 70% inhibition of iodine uptake have no apparent effect on human T4 levels. Thus, the use of this study as the primary basis of the RfD is problematic. Nevertheless, a benchmark dose of 0.01 mg/kg-day was identified in this clinical study, which supports a threshold value of 0.006 mg/kg-day identified by its authors and the RfD of 0.002 mg/kg-day estimated in this paper.

Administration, Oral↗