Inference of putative cell-type-specific imprinted regulatory elements and genes during human neuronal differentiation.

Genomic imprinting results in gene expression bias caused by parental chromosome of origin and occurs in genes with important roles during human brain development. However, the cell-type and temporal specificity of imprinting during human neurogenesis is generally unknown. By detecting within-donor allelic biases in chromatin accessibility and gene expression that are unrelated to cross-donor genotype, we inferred imprinting in both primary human neural progenitor cells and their differentiated neuronal progeny from up to 85 donors. We identified 43/20 putatively imprinted regulatory elements (IREs) in neurons/progenitors, and 133/79 putatively imprinted genes in neurons/progenitors. Although 10 IREs and 42 genes were shared between neurons and progenitors, most putative imprinting was only detected within specific cell types. In addition to well-known imprinted genes and their promoters, we inferred novel putative IREs and imprinted genes. Consistent with both DNA methylation-based and H3K27me3-based regulation of imprinted expression, some putative IREs also overlapped with differentially methylated or histone-marked regions. Finally, we identified a progenitor-specific putatively imprinted gene overlapping with copy number variation that is associated with uniparental disomy-like phenotypes. Our results can therefore be useful in interpreting the function of variants identified in future parent-of-origin association studies.

Fetal Origins of Health Disparities: Transgenerational Consequences of Racism.

Despite advances in perinatal medicine, racial disparity in birth outcomes remains a public health problem in the USA. The underlying mechanisms for this long-standing racial disparity are incompletely understood. This review presents transgenerational risk factors for racial disparities in preterm birth, exploring the impact of interpersonal and structural racism, theoretical models of stress, and biological markers of racial disparities.

Racial and Ethnic Inequities in Therapeutic Hypothermia and Neonatal Hypoxic-Ischemic Encephalopathy: A Retrospective Cohort Study.

OBJECTIVE: To investigate racial inequities in the use of therapeutic hypothermia (TH) and outcomes in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: We queried an administrative birth cohort of mother-baby pairs in California from 2010 through 2019 using International Classification of Diseases codes to evaluate the association between race and ethnicity and the application of TH in infants with HIE. We identified 4779 infants with HIE. Log-linear regression was used to calculate risk ratios (RR) for TH, adjusting for hospital transfer, rural location, gestational age between 35 and 37 weeks, and HIE severity. Risk of adverse infant outcome was calculated by race and ethnicity and stratified by TH. RESULTS: From our identified cohort, 1338 (28.0%) neonates underwent TH. White infants were used as the reference sample, and 410 (28.4%) received TH. Black infants were significantly less likely to receive TH with 74 (20.0%) with an adjusted risk ratio (aRR) of 0.7 (95% CI 0.5-0.9). Black infants with any HIE who did not receive TH were more likely to have a hospital readmission (aRR 1.36, 95% CI 1.10-1.68) and a tracheostomy (aRR 3.07, 95% CI 1.19-7.97). Black infants with moderate/severe HIE who did not receive TH were more likely to have cerebral palsy (aRR 2.72, 95% CI 1.07-6.91). CONCLUSIONS: In this study cohort, Black infants with HIE were significantly less likely to receive TH. Black infants also had significantly increased risk of some adverse outcomes of HIE. Possible reasons for this inequity include systemic barriers to care and systemic bias.

MRLocus: Identifying causal genes mediating a trait through Bayesian estimation of allelic heterogeneity.

Expression quantitative trait loci (eQTL) studies are used to understand the regulatory function of non-coding genome-wide association study (GWAS) risk loci, but colocalization alone does not demonstrate a causal relationship of gene expression affecting a trait. Evidence for mediation, that perturbation of gene expression in a given tissue or developmental context will induce a change in the downstream GWAS trait, can be provided by two-sample Mendelian Randomization (MR). Here, we introduce a new statistical method, MRLocus, for Bayesian estimation of the gene-to-trait effect from eQTL and GWAS summary data for loci with evidence of allelic heterogeneity, that is, containing multiple causal variants. MRLocus makes use of a colocalization step applied to each nearly-LD-independent eQTL, followed by an MR analysis step across eQTLs. Additionally, our method involves estimation of the extent of allelic heterogeneity through a dispersion parameter, indicating variable mediation effects from each individual eQTL on the downstream trait. Our method is evaluated against other state-of-the-art methods for estimation of the gene-to-trait mediation effect, using an existing simulation framework. In simulation, MRLocus often has the highest accuracy among competing methods, and in each case provides more accurate estimation of uncertainty as assessed through interval coverage. MRLocus is then applied to five candidate causal genes for mediation of particular GWAS traits, where gene-to-trait effects are concordant with those previously reported. We find that MRLocus's estimation of the causal effect across eQTLs within a locus provides useful information for determining how perturbation of gene expression or individual regulatory elements will affect downstream traits. The MRLocus method is implemented as an R package available at https://mikelove.github.io/mrlocus.

Genome-Wide Association Study of Age-Related Macular Degeneration Reveals 2 New Loci Implying Shared Genetic Components with Central Serous Chorioretinopathy.

PURPOSE: To investigate the genetic architecture of age-related macular degeneration (AMD) in a Japanese population. DESIGN: Genome-wide association study (GWAS). PARTICIPANTS: Three thousand seven hundred seventy-two patients with AMD and 16 770 control participants from the Japanese population were enrolled in the association analyses. METHODS: We conducted a meta-analysis of 2 independent GWASs that included a total of 2663 patients with AMD and 9471 control participants using the imputation reference panel for genotype imputation specified for the Japanese population (n = 3541). A replication study was performed using an independent set of 1109 patients with AMD and 7299 control participants. MAIN OUTCOME MEASURES: Associations of genetic variants with AMD. RESULTS: A meta-analysis of the 2 GWASs identified 6 loci significantly associated with AMD (P < 5.0 × 10-8). Of these loci, 4 were known to be associated with AMD (CFH, C2/FB, TNFRSF10A, and ARMS2), and 2 were novel (rs4147157 near WBP1L and rs76228488 near GATA5). The newly identified associations were confirmed in a replication study (P < 0.01). After the meta-analysis of all datasets, we observed strong associations in these loci (P = 1.88 × 10-12 and P = 1.35 × 10-9 for meta-analysis for rs4147157 and rs76228488, respectively). When we looked up the associations in the reported central serous chorioretinopathy (CSC) GWAS conducted in the Japanese population, both loci were associated significantly with CSC (P = 4.86 × 10-3 and P = 4.28 × 10-3 for rs4147157 and rs76228488, respectively). We performed a genetic colocalization analysis for these loci and estimated that the posterior probabilities of shared causal variants between AMD and CSC were 0.39 and 0.60 for WBP1L and GATA5, respectively. Genetic correlation analysis focusing on the epidemiologically suggested clinical risk factors implicated shared polygenic architecture between AMD and smoking cessation (rg [the measure of genetic correlation] = -0.33; P = 0.01; false discovery rate, 0.099). CONCLUSIONS: Our findings imply shared genetic components conferring the risk of both AMD and CSC. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The Relation of Neighborhood Racial and Income Polarity to Preterm Birth Rates in Chicago.

OBJECTIVES: To investigate the extent to which spatial social polarization is associated with preterm birth among urban African-American and non-Latinx white women, and whether prenatal care modifies this relationship. METHODS: We performed multilevel logistic regression analyses on a 2013-2017 dataset of Chicago vital records (N = 29,179) with appended Index of Concentration at the Extremes (ICE) values for race and income. RESULTS: Women who resided in the bottom ICE quintile neighborhoods had a preterm birth rate of 11.5%, compared to 7.3% for those who live in the top ICE quintile areas; adjusted odds ratio (aOR) equaled 1.72 (95% confidence interval [CI] = 1.39, 2.12). This disparity widened for early (< 34 weeks) preterm birth rates, aOR = 2.60 (1.77, 3.81). These associations persisted among women with adequate prenatal care utilization. CONCLUSIONS FOR PRACTICE: Spatial polarization of race and income in urban African-American and non-Latinx white women's residential environment is strongly associated with preterm birth rates, even among those who receive adequate prenatal care. These findings highlight the benefit of using ICE to contextualize the impact of urban neighborhood-level characteristics on preterm birth rates.

Endogenization and excision of human herpesvirus 6 in human genomes.

Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactivate into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.

Evaluating brain structure traits as endophenotypes using polygenicity and discoverability.

Human brain structure traits have been hypothesized to be broad endophenotypes for neuropsychiatric disorders, implying that brain structure traits are comparatively "closer to the underlying biology." Genome-wide association studies from large sample sizes allow for the comparison of common variant genetic architectures between traits to test the evidence supporting this claim. Endophenotypes, compared to neuropsychiatric disorders, are hypothesized to have less polygenicity, with greater effect size of each susceptible SNP, requiring smaller sample sizes to discover them. Here, we compare polygenicity and discoverability of brain structure traits, neuropsychiatric disorders, and other traits (91 in total) to directly test this hypothesis. We found reduced polygenicity (FDR = 0.01) and increased discoverability (FDR = 3.68 × 10-9 ) of cortical brain structure traits, as compared to aggregated estimates of multiple neuropsychiatric disorders. We predict that ~8 M individuals will be required to explain the full heritability of cortical surface area by genome-wide significant SNPs, whereas sample sizes over 20 M will be required to explain the full heritability of depression. In conclusion, our findings are consistent with brain structure satisfying the higher power criterion of endophenotypes.

Teen Birth Across Generations Among Non-Latino Whites and African-American Women: The Effect of Race and Neighborhood Income.

OBJECTIVES: To examine the extent to which lifelong neighborhood income modifies the generational association of teen birth among White and AA women in Cook County, IL. METHODS: Stratified and multilevel logistic regression analyses were conducted on the Illinois transgenerational dataset of singleton births (1989-1991) to non-Latina White and AA mothers (born 1956-1976) with appended U.S. census income information. We calculated rates and risks of teen births according to race, maternal age, and lifelong neighborhood economic environment. RESULTS: Teen birth occurred at a rate of 9.5% and 52.9% for White and AA women, respectively. White women whose mothers were teens when they were born had an over five-fold increased risk of becoming teen mothers themselves. For AA women, the risk was smaller, but statistically significant. For both races, women who experienced downward economic mobility had the highest risk of teen birth, while women with upward mobility had the lowest risk, even compared to women in lifelong high income neighborhoods. While White women exposed to lifelong low income had almost threefold increased risk of teen birth compared to those in lifelong high income neighborhoods, AA women in lifelong high and lifelong low income neighborhoods had similar risk of teen birth. CONCLUSIONS FOR PRACTICE: Understanding the racial differences in intergenerational patterns of teen birth is important for effective program planning and policy making, given that interventions targeted at daughters of teen mothers may differ in effectiveness for White and AA teens.

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Center, Gestational Age, and Race Impact End-of-Life Care Practices at Regional Neonatal Intensive Care Units.

OBJECTIVE: To assess the impact of intercenter variation and patient factors on end-of-life care practices for infants who die in regional neonatal intensive care units (NICUs). STUDY DESIGN: We conducted a retrospective cohort analysis using the Children's Hospital Neonatal Database during 2010-2016. A total of 6299 nonsurviving infants cared for in 32 participating regional NICUs were included to examine intercenter variation and the effects of gestational age, race, and cause of death on 3 end-of-life care practices: do not attempt resuscitation orders (DNR), cardiopulmonary resuscitation within 6 hours of death (CPR), and withdrawal of life-sustaining therapies (WLST). Factors associated with these practices were used to develop a multivariable equation. RESULTS: Dying infants in the cohort underwent DNR (55%), CPR (21%), and WLST (73%). Gestational age, cause of death, and race were significantly and differently associated with each practice: younger gestational age (<28 weeks) was associated with CPR (OR 1.7, 95% CI 1.5-2.1) but not with DNR or WLST, and central nervous system injury was associated with DNR (1.6, 1.3-1.9) and WLST (4.8, 3.7-6.2). Black race was associated with decreased odds of WLST (0.7, 0.6-0.8). Between centers, practices varied widely at different gestational ages, race, and causes of death. CONCLUSIONS: From the available data on end-of-life care practices for regional NICU patients, variability appears to be either individualized or without consistency.

Neighborhood Gun Violence and Birth Outcomes in Chicago.

OBJECTIVES: To examine the association between gun violence and birth outcomes among women in Chicago. METHODS: Using a 5-year set of birth files (2011-2015) merged with census and police data, birth outcomes including low birth weight (LBW, BW < 2500 g), preterm birth (PTB, < 37 weeks gestation), and small-for-gestational-age (SGA, BW < 10th percentile) were examined among non-Hispanic (NH) white, NH black, and Hispanic women in Chicago. Gun violence rates were categorized into tertiles. Multilevel, multiple logistic regression examined the effects of gun violence and race/ethnicity on birth outcomes. RESULTS: Of 175,065 births, 10.6% of LBW, 10.6% of PTB, and 9.1% of SGA occurred in high violence tertile. Using white women in low violence tertile as reference, the OR for LBW among black women ranged 1.9-2.1 across all tertiles, and 0.8-1.2 among Hispanic women. OR for PTB for black women were 1.6-1.7 and 1.0-1.2 for Hispanic women, and OR for SGA for black women were 1.6-1.7 and for Hispanic women 0.9-1.0. CONCLUSIONS FOR PRACTICE: In Chicago, race/ethnicity was associated with birth outcomes, regardless of the level of exposure to gun violence, in 2011-2015. The differences in racial/ethnic composition across the violence exposure levels suggest that, rather than gun violence alone, residential segregation and the geographic inequities likely contribute to disparate birth outcomes.

African-American:White Disparity in Infant Mortality due to Congenital Heart Disease.

OBJECTIVE: To determine the importance of infant factors, maternal prenatal care use, and demographic characteristics in explaining the racial disparity in infant (age <365 days) mortality due to congenital heart defects (CHD). STUDY DESIGN: In this cross-sectional population-based study, stratified and multivariable logistic regression analyses were performed on the 2003-2004 National Center for Health Statistics linked live birth-infant death cohort files of term infants with non-Hispanic white (n = 3 684 569) and African-American (n = 782 452) US-born mothers. Infant mortality rate, including its neonatal (<28 day) and postneonatal (28-364 day) components, due to CHD was the outcome measured. RESULTS: The infant mortality rate due to CHD for African-American infants (296 deaths; 3.78 per 10 000 live births) exceeded that of white infants (1025 deaths; 2.78 per 10 000 live births) (relative risk [RR], 1.36; 95% CI, 1.20-1.55). The racial disparity was wider in the postneonatal period (2.08 per 10 000 vs 1.42 per 10 000; RR, 1.53; 95% CI, 1.29-1.83) compared with the neonatal period (1.70 per 10 000 vs 1.44 per 10 000; RR, 1.20; 95% CI, 0.99-1.45). Compared with white mothers, African-American mothers had a higher percentage of high-risk characteristics. In multivariable logistic regression models, the adjusted OR of postneonatal and neonatal mortality due to CHD for African-American mothers compared with white mothers was 1.20 (95% CI, 0.98-1.48) and 0.95 (95% CI, 0.77-1.19), respectively. CONCLUSION: The racial disparity in infant mortality rate due to CHD among term infants with US-born mothers is driven predominately by the postneonatal survival disadvantage of African-American infants. Commonly cited individual-level risk factors partly explain this phenomenon. The study is limited by the lack of information on neighborhood factors.

Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

AIM: Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. METHODS: We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. RESULTS: Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. CONCLUSION: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.

Early introduction of complementary foods in preterm infants.

OBJECTIVES: The aim of the present study was to determine the odds of early introduction of solid foods in a nationally representative sample of preterm infants when compared with term infants and to examine whether factors associated with early introduction are the same for preterm and term infants. METHODS: Our sample of 7650 came from the first wave of the Early Childhood Longitudinal Study, Birth Cohort (2001-2002). We performed multivariable logistic regression to determine whether preterm infants were introduced to solid foods more frequently before 4 months than term infants using adjusted age for preterm infants and chronological age for term infants. In a separate analysis in preterm infants, we used multivariable logistic regression to determine whether the factors associated with early introduction in term infants were the same in the preterm sample. RESULTS: Infants born 22 to 32 weeks' gestation had a 9.90 (95% confidence interval 5.54-18.0) odds of being fed solid food before 4 months compared with term infants, and infants born 33 to 36 weeks' gestation had a 6.19 (95% confidence interval 4.58-8.36) odds. Race/ethnicity and maternal smoking were the only factors that predicted early solid feeding in both preterm and term infants; the remaining predictors differed. CONCLUSIONS: Preterm infants are significantly more likely to be introduced to complementary foods early compared with term infants. The predictors of early solid feeding differ for preterm infants. Given the health implications, specific guidelines for preterm infants should be developed and future research should examine predictors of early introduction in preterm infants.

Social Determinants of Premature Birth.

Social determinants of health have received increasing attention in public health, leading to increased understanding of how social factors-individual and contextual-shape the health of the mother and infant. However, racial differences in birth outcomes persist, with incomplete explanation for the widening disparity. Here, we highlight the social determinants of preterm birth, with special attention to the social experiences among African American women, which are likely attributed to structural racism and discrimination throughout life.

Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain.

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

Wnt activity reveals context-specific genetic effects on gene regulation in neural progenitors.

Gene regulatory effects in bulk-post mortem brain tissues are undetected at many non-coding brain trait-associated loci. We hypothesized that context-specific genetic variant function during stimulation of a developmental signaling pathway would explain additional regulatory mechanisms. We measured chromatin accessibility and gene expression following activation of the canonical Wnt pathway in primary human neural progenitors from 82 donors. TCF/LEF motifs, brain structure-, and neuropsychiatric disorder-associated variants were enriched within Wnt-responsive regulatory elements (REs). Genetically influenced REs were enriched in genomic regions under positive selection along the human lineage. Stimulation of the Wnt pathway increased the detection of genetically influenced REs/genes by 66.2%/52.7%, and led to the identification of 397 REs primed for effects on gene expression. Context-specific molecular quantitative trait loci increased brain-trait colocalizations by up to 70%, suggesting that genetic variant effects during early neurodevelopmental patterning lead to differences in adult brain and behavioral traits.

Cellular Genome-wide Association Study Identifies Common Genetic Variation Influencing Lithium-Induced Neural Progenitor Proliferation.

BACKGROUND: Bipolar disorder is a highly heritable neuropsychiatric condition affecting more than 1% of the human population. Lithium salts are commonly prescribed as a mood stabilizer for individuals with bipolar disorder. Lithium is clinically effective in approximately half of treated individuals, and their genetic backgrounds are known to influence treatment outcomes. While the mechanism of lithium's therapeutic action is unclear, it stimulates adult neural progenitor cell proliferation, similar to some antidepressant drugs. METHODS: To identify common genetic variants that modulate lithium-induced proliferation, we conducted an EdU incorporation assay in a library of 80 genotyped human neural progenitor cells treated with lithium. These data were used to perform a genome-wide association study to identify common genetic variants that influence lithium-induced neural progenitor cell proliferation. We manipulated the expression of a putatively causal gene using CRISPRi/a (clustered regularly interspaced short palindromic repeats interference/activation) constructs to experimentally verify lithium-induced proliferation effects. RESULTS: We identified a locus on chr3p21.1 associated with lithium-induced proliferation. This locus is also associated with bipolar disorder risk, schizophrenia risk, and interindividual differences in intelligence. We identified a single gene, GNL3, whose expression temporally increased in an allele-specific fashion following lithium treatment. Experimentally increasing the expression of GNL3 led to increased proliferation under baseline conditions, while experimentally decreasing GNL3 expression suppressed lithium-induced proliferation. CONCLUSIONS: Our experiments reveal that common genetic variation modulates lithium-induced neural progenitor proliferation and that GNL3 expression is necessary for the full proliferation-stimulating effects of lithium. These results suggest that performing genome-wide associations in genetically diverse human cell lines is a useful approach to discover context-specific pharmacogenomic effects.