Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

STAT5 activation promotes progression and chemotherapy resistance in early T-cell precursor acute lymphoblastic leukemia.

Interleukin-7 (IL-7) supports the growth and chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL), particularly the early T-cell precursor subtype (ETP-ALL), which frequently has activating mutations of IL-7 signaling. Signal transducer and activator of transcription (STAT5) is an attractive therapeutic target because it is almost universally activated in ETP-ALL, even in the absence of mutations of upstream activators such as the IL-7 receptor (IL-7R), Janus kinase, and Fms-like tyrosine kinase 3 (FLT3). To examine the role of activated STAT5 in ETP-ALL, we have used a Lmo2-transgenic (Lmo2Tg) mouse model in which we can monitor chemoresistant preleukemia stem cells (pre-LSCs) and leukemia stem cells (LSCs) that drive T-ALL development and relapse following chemotherapy. Using IL-7R-deficient Lmo2Tg mice, we show that IL-7 signaling was not required for the formation of pre-LSCs but essential for their expansion and clonal evolution into LSCs to generate T-ALL. Activated STAT5B was sufficient for the development of T-ALL in IL-7R-deficient Lmo2Tg mice, indicating that inhibition of STAT5 is required to block the supportive signals provided by IL-7. To further understand the role of activated STAT5 in LSCs of ETP-ALL, we developed a new transgenic mouse that enables T-cell specific and doxycycline-inducible expression of the constitutively activated STAT5B1∗6 mutant. Expression of STAT5B1∗6 in T cells had no effect alone but promoted expansion and chemoresistance of LSCs in Lmo2Tg mice. Pharmacologic inhibition of STAT5 with pimozide-induced differentiation and loss of LSCs, while enhancing response to chemotherapy. Furthermore, pimozide significantly reduced leukemia burden in vivo and overcame chemoresistance of patient-derived ETP-ALL xenografts. Overall, our results demonstrate that STAT5 is an attractive therapeutic target for eradicating LSCs in ETP-ALL.

Genome-wide transcription factor-binding maps reveal cell-specific changes in the regulatory architecture of human HSPCs.

Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay among transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs (FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2) bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remains unknown. We mapped genome-wide chromatin contacts (HiC, H3K27ac, HiChIP), chromatin modifications (H3K4me3, H3K27ac, H3K27me3) and 10 TF binding profiles (heptad, PU.1, CTCF, STAG2) in HSPC subsets (stem/multipotent progenitors plus common myeloid, granulocyte macrophage, and megakaryocyte erythrocyte progenitors) and found TF occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. Furthermore, heptad-occupied regions in HSPCs were subsequently bound by lineage-defining TFs, including PU.1 and GATA1, suggesting that heptad factors may prime regulatory elements for use in mature cell types. We also found that enhancers with cell-type-specific heptad occupancy shared a common grammar with respect to TF binding motifs, suggesting that combinatorial binding of TF complexes was at least partially regulated by features encoded in DNA sequence motifs. Taken together, this study comprehensively characterizes the gene regulatory landscape in rare subpopulations of human HSPCs. The accompanying data sets should serve as a valuable resource for understanding adult hematopoiesis and a framework for analyzing aberrant regulatory networks in leukemic cells.

Investigation of Recessive Effects of Coding Variants on Common Clinical Phenotypes in Exome-Sequenced UK Biobank Participants.

INTRODUCTION: Previous studies have demonstrated effects of rare coding variants on common, clinically relevant phenotypes although the additive burden of these variants makes only a small contribution to overall trait variance. Although recessive effects of individual homozygous variants have been studied, little work has been done to elucidate the impact of rare coding variants occurring together as compound heterozygotes. METHODS: In this study, attempts were made to identify pairs of variants likely to be occurring as compound heterozygotes using 200,000 exome-sequenced subjects from the UK Biobank. Pairs of variants, which were seen together in the same subject more often than would be expected by chance, were excluded as it was assumed that these might be present in the same haplotype. Attention was restricted to variants with minor allele frequency ≤0.05 and to those predicted to alter amino acid sequence or prevent normal gene expression. For each gene, compound heterozygotes were assigned scores based on the rarity and predicted functional consequences of the constituent variants and the scores were used in a logistic regression analysis to test for association with hypertension, hyperlipidaemia, and type 2 diabetes. RESULTS: No statistically significant associations were observed and the results conformed to the distribution, which would be expected under the null hypothesis. The average number of apparently compound heterozygous subjects for each gene was only 282.2. CONCLUSION: It seems difficult to detect an effect of compound heterozygotes on the risk of these phenotypes. Even if recessive effects from compound heterozygotes do occur, they would only affect a small number of people and overall would not make a substantial contribution to phenotypic variance. This research has been conducted using the UK Biobank Resource.

Weighted burden analysis of rare coding variants in 470,000 exome-sequenced UK Biobank participants characterises effects on hyperlipidaemia risk.

A previous study of 200,000 exome-sequenced UK Biobank participants investigating the association between rare coding variants and hyperlipidaemia had implicated four genes, LDLR, PCSK9, APOC3 and IFITM5, at exome-wide significance. In addition, a further 43 protein-coding genes were significant with an uncorrected p value of <0.001. Exome sequence data has become available for a further 270,000 participants and weighted burden analysis to test for association with hyperlipidaemia was carried out in this sample for the 47 genes highlighted by the previous study. There was no evidence to implicate IFITM5 but LDLR, PCSK9, APOC3, ANGPTL3, ABCG5 and NPC1L1 were all statistically significant after correction for multiple testing. These six genes were also all exome-wide significant in the combined sample of 470,000 participants. Variants impairing function of LDLR and ABCG5 were associated with increased risk whereas variants in the other genes were protective. Variant categories associated with large effect sizes are cumulatively very rare and the main benefit of this kind of study seems to be to throw light on the molecular mechanisms impacting hyperlipidaemia risk, hopefully supporting attempts to develop improved therapies.

Highly public anti-Black violence is associated with poor mental health days for Black Americans.

Highly public anti-Black violence in the United States may cause widely experienced distress for Black Americans. This study identifies 49 publicized incidents of racial violence and quantifies national interest based on Google searches; incidents include police killings of Black individuals, decisions not to indict or convict the officer involved, and hate crime murders. Weekly time series of population mental health are produced for 2012 through 2017 using two sources: 1) Google Trends as national search volume for psychological distress terms and 2) the Behavioral Risk Factor Surveillance System (BRFSS) as average poor mental health days in the past 30 d among Black respondents (mean weekly sample size of 696). Autoregressive moving average (ARMA) models accounted for autocorrelation, monthly unemployment, season and year effects, 52-wk lags, news-related searches for suicide (for Google Trends), and depression prevalence and percent female (for BRFSS). National search interest varied more than 100-fold between racial violence incidents. Black BRFSS respondents reported 0.26 more poor mental health days during weeks with two or more racial incidents relative to none, and 0.13 more days with each log10 increase in national interest. Estimates were robust to sensitivity tests, including controlling for monthly number of Black homicide victims and weekly search interest in riots. As expected, racial incidents did not predict average poor mental health days among White BRFSS respondents. Results with national psychological distress from Google Trends were mixed but generally unsupportive of hypotheses. Reducing anti-Black violence may benefit Black Americans' mental health nationally.

Social inequities in neighborhood health amenities over time in the Wasatch Front Region of Utah: Historical inequities, population selection, or differential investment?

Socially disadvantaged groups generally are more likely to reside in areas with less desirable conditions. We examined longitudinal relationships between neighborhood resident characteristics and amenities from 1990 to 2010 in an urban area of Utah, U.S. Four temporal patterns of social inequities are described using mixed-effects models: historical inequities; differential selection into amenity-rich tracts; differential investment in amenities; and simultaneous twenty-year change. Results indicate historical differences by neighborhood socioeconomic status, with lower status tracts having fewer green/natural amenities and higher air pollution in 1990 but also greater walkability and more food stores. Differences in amenities by neighborhood socioeconomic status widened over time as aggregate socioeconomic status disproportionately increased in tracts with more green/natural amenities, less air pollution, and lower walkability in 1990, consistent with differential selection. Tract percentage non-Hispanic White did not predict historical differences, but tracts that were less walkable and had fewer healthy food stores in 1990 experienced larger subsequent increases in racial/ethnic diversity. Tracts with higher relative to lower percentage non-Hispanic White in 1990 had larger decreases in air pollution but declining green/natural amenities. This study shows how social inequities in neighborhood amenities change over time, providing evidence of historical socioeconomic differences increasing from differential resident selection.

Reduction is sufficient for the disassembly of ricin and Shiga toxin 1 but not Escherichia coli heat-labile enterotoxin.

Many AB toxins contain an enzymatic A moiety that is anchored to a cell-binding B moiety by a disulfide bridge. After receptor-mediated endocytosis, some AB toxins undergo retrograde transport to the endoplasmic reticulum (ER) where reduction of the disulfide bond occurs. The reduced A subunit then dissociates from the holotoxin and enters the cytosol to alter its cellular target. Intoxication requires A chain separation from the holotoxin, but, for many toxins, it is unclear if reduction alone is sufficient for toxin disassembly. Here, we examined the link between reduction and disassembly for several ER-translocating toxins. We found disassembly of the reduced Escherichia coli heat-labile enterotoxin (Ltx) required an interaction with one specific ER-localized oxidoreductase: protein disulfide isomerase (PDI). In contrast, the reduction and disassembly of ricin toxin (Rtx) and Shiga toxin 1 (Stx1) were coupled events that did not require PDI and could be triggered by reductant alone. PDI-deficient cells accordingly exhibited high resistance to Ltx with continued sensitivity to Rtx and Stx1. The distinct structural organization of each AB toxin thus appears to determine whether holotoxin disassembly occurs spontaneously upon disulfide reduction or requires the additional input of PDI.

Analysis of 200 000 exome-sequenced UK Biobank subjects illustrates the contribution of rare genetic variants to hyperlipidaemia.

Background A few genes have previously been identified in which very rare variants can have major effects on lipid levels. Methods Weighted burden analysis of rare variants was applied to exome sequenced UK Biobank subjects with hyperlipidaemia as the phenotype, of whom 44 054 were designated cases and 156 578 controls, with the strength of association characterised by the signed log 10 p value (SLP). Results With principal components included as covariates there was a tendency for genes on the X chromosome to produce strongly negative SLPs, and this was found to be due to the fact that rare X chromosome variants were identified less frequently in men than women. The test performed well when both principal components and sex were included as covariates and strongly implicated LDLR (SLP=50.08) and PCSK9 (SLP=-10.42) while also highlighting other genes previously found to be associated with lipid levels. Variants classified by SIFT as deleterious have on average a twofold effect and their cumulative frequency is such that they are present in approximately 1.5% of the population. Conclusion These analyses shed further light on the way that genetic variation contributes to risk of hyperlipidaemia and in particular that there are very many protein-altering variants which have on average moderate effects and whose effects can be detected when large samples of exome-sequenced subjects are available. This research has been conducted using the UK Biobank Resource.

Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1, NOP10, or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.

Lean legacy, heavy heritage: family history of diabetes and its association with young adult body mass index.

Substantial intergenerational transmission of diabetes mellitus (DM) risk exists. However, less is known regarding whether parental DM and DM among extended family members relate to adult offspring's body mass index (BMI), and whether any of these associations vary by sex. Using data from the National Longitudinal Study of Youth 1997 cohort (NLSY97), we assess the sex-specific relationship between DM present in first-degree parents and second-degree relatives and BMI among the parents' young adult offspring.Multivariate regressions reveal a positive relationship between parental DM and young adults' BMI for both daughters and sons, and the magnitude of coefficients is somewhat larger for the same-sex parent. Further, we observe that the link between parental DM and young adults' BMI is strongest when both parents have diagnosed diabetes. In contrast, the relationship between second-degree relatives with DM and the respondent's BMI is weaker and appears to be sex-specific, through same-sex parent and respondent. Logistic regressions show the association is especially strong when assessing how parental DM status relates to young adults' obesity risk. These results generally persist when controlling for parental BMI. The findings of this study point to the need to better distinguish the role of shared family environments (e.g., eating and physical activity patterns) from shared genes in order to understand factors that may influence young adults' BMI. Young adult offspring of parents with diabetes should be targeted for obesity prevention efforts in order to reduce their risks of obesity and perhaps diabetes.

Peer-Based Intervention for Socioemotional Concerns Among Children with ADHD.

This study examined the potential benefits of peer-based dyadic interventions for improving the socioemotional functioning of children with ADHD. Participants included children ages 8-12 diagnosed with ADHD-combined type (n = 34) pooled from a larger randomized study comparing peer-based dyadic interventions. Self-concept and depressive symptoms were evaluated at pre- and post-treatment using single group design. Results showed significantly positive child responses to intervention for self-concept. Further, improvements in self-concept were not moderated by the type of dyadic intervention received or by treatment related changes in externalizing behaviors. The severity of reported depressive symptoms, however, did not significantly change. This suggests therapeutic interaction with peers, as demonstrated in peer-based dyadic intervention models, can improve self-concept in children with ADHD even when socioemotional concerns are not a primary target of treatment and independent of behavioral outcomes achieved. These preliminary findings support promoting prosocial peer behavior as a critical domain for ADHD intervention for children.

Social scientists would do well to steer clear of polygenic scores.

The problems with polygenic scores (PGSs) have been understated. The fact that they are ancestry-specific means that biases related to sociodemographic factors would be impossible to avoid. Additionally, the requirement to obtain DNA would have profound impacts on study design and required resources, as well as likely introducing recruitment bias. PGSs are unhelpful for social science research.

Study of variants in genes implicated in rare familial migraine syndromes and their association with migraine in 200,000 exome-sequenced UK Biobank participants.

BACKGROUND: A number of genes have been implicated in rare familial syndromes which have migraine as part of their phenotype but these genes have not previously been implicated in the common form of migraine. METHODS: Among exome-sequenced participants in the UK Biobank, we identified 7194 migraine cases with the remaining 193,433 participants classified as controls. We investigated rare variants in 10 genes previously reported to be implicated in conditions with migraine as a prominent part of the phenotype and carried out gene- and variant-based tests for association. RESULTS: We found no evidence for association of these genes or variants with the common form of migraine seen in our subjects. In particular, a frameshift variant in KCNK18, p.(Phe139Trpfs*24), which had been shown to segregate with migraine with aura in a multiply affected pedigree, was found in 196 (0.10%) controls as well as in 10 (0.14%) cases (χ2  = 0.96, 1 df, p = 0.33). CONCLUSIONS: Since there is no other reported evidence to implicate KCNK18, we conclude that this gene and its product, TRESK, should no longer be regarded as being involved in migraine aetiology. Overall, we do not find that rare, functional variants in genes previously implicated to be involved in familial syndromes including migraine as part of the phenotype make a contribution to the commoner forms of migraine observed in this population.

Weighted burden analysis in 200,000 exome-sequenced subjects characterises rare variant effects on BMI.

INTRODUCTION: A number of genes have been identified in which rare variants can cause obesity. Here we analyse a sample of exome sequenced subjects from UK Biobank using BMI as a phenotype with the aims of identifying genes in which rare, functional variants influence BMI and characterising the effects of different categories of variant. METHODS: There were 199,807 exome sequenced subjects for whom BMI was recorded. Weighted burden analysis of rare, functional variants was carried out, incorporating population principal components and sex as covariates. For selected genes, additional analyses were carried out to clarify the contribution of different categories of variant. Statistical significance was summarised as the signed log 10 of the p value (SLP), given a positive sign if the weighted burden score was positively correlated with BMI. RESULTS: Two genes were exome-wide significant, MC4R (SLP = 15.79) and PCSK1 (SLP = 6.61). In MC4R, disruptive variants were associated with an increase in BMI of 2.72 units and probably damaging nonsynonymous variants with an increase of 2.02 units. In PCSK1, disruptive variants were associated with a BMI increase of 2.29 and protein-altering variants with an increase of 0.34. Results for other genes were not formally significant after correction for multiple testing, although SIRT1, ZBED6 and NPC2 were noted to be of potential interest. CONCLUSION: Because the UK Biobank consists of a self-selected sample of relatively healthy volunteers, the effect sizes noted may be underestimates. The results demonstrate the effects of very rare variants on BMI and suggest that other genes and variants will be definitively implicated when the sequence data for additional subjects becomes available.

Clinical integration of patient-reported outcome measures to enhance the care of patients with SLE: a multi-centre prospective cohort study.

OBJECTIVE: To assess the feasibility and impact of integrating electronic patient-reported outcome measures (PROMs) into the routine outpatient care of patients with SLE. METHODS: We conducted a prospective cohort study, utilizing a mixed-methods sequential explanatory design, of SLE outpatients receiving rheumatology care at two academic medical centres. Participants completed electronic PROMs at enrolment and then prior to their next two routine rheumatology visits. PROM score reports were shared with patients and rheumatologists before visits. Patients and rheumatologists completed post-visit surveys evaluating the utility of PROMs in the clinical encounters. Focus groups of patients and interviews with treating rheumatologists were conducted to further explore their experience utilizing PROMs. RESULTS: A total of 105 SLE patients and 17 rheumatologists participated in the study. Patients completed PROMs in 159 of 184 encounters (86%), with 93% of surveys completed remotely. Patients reported that PROMs were 'quite a bit' or 'very' useful (55% of encounters) and beneficial to communication (55% of encounters). In contrast, physicians found PROMs useful (20%) and beneficial to communication (17%) less frequently. There was no significant change in visit length, health-related quality of life or disease activity after implementation of PROMs; however, patient satisfaction improved slightly. Qualitative analyses revealed that patients felt PROMs provided utility primarily by facilitating communication, particularly when physicians discussed the surveys. CONCLUSION: The remote capture and integration of electronic PROMs into clinical care was feasible in a diverse cohort of SLE outpatients. PROMs were useful to patients and enhanced their clinical experience primarily by facilitating communication.

The EMT modulator SNAI1 contributes to AML pathogenesis via its interaction with LSD1.

Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML.

Analysis of rare coding variants in 200,000 exome-sequenced subjects reveals novel genetic risk factors for type 2 diabetes.

AIMS: The study aimed to elucidate the effects of rare genetic variants on the risk of type 2 diabetes (T2D). MATERIALS AND METHODS: Weighted burden analysis of rare variants was applied to a sample of 200,000 exome-sequenced participants in the UK Biobank project, of whom over 13,000 were identified as having T2D. Variant weights were allocated based on allele frequency and predicted effect, as informed by a previous analysis of hyperlipidaemia. RESULTS: There was an exome-wide significant increased burden of rare, functional variants in three genes, GCK, HNF4A and GIGYF1. GIGYF1 has not previously been identified as a diabetes risk gene and its product appears to be involved in the modification of insulin signalling. A number of other genes did not attain exome-wide significance but were highly ranked and potentially of interest, including ALAD, PPARG, GYG1 and GHRL. Loss of function (LOF) variants were associated with T2D in GCK and GIGYF1 whereas nonsynonymous variants annotated as probably damaging were associated in GCK and HNF4A. Overall, fewer than 1% of T2D cases carried one of these variants. In HNF1A and HNF1B there was an excess of LOF variants among cases but the small numbers of these fell short of statistical significance. CONCLUSIONS: Rare genetic variants make an identifiable contribution to T2D in a small number of cases but these may provide valuable insights into disease mechanisms. As larger samples become available it is likely that additional genetic factors will be identified.

Identification of specific genes involved in schizophrenia aetiology - what difference does it make?

Genes in which rare, damaging variants substantially increase risk of developing schizophrenia have now been identified. These findings can influence how we think about mental illness in general as well as yielding specific insights into schizophrenia aetiology. Better understanding of underlying biology might eventually lead to improved treatments.

Does a Rising Median Income Lift All Birth Weights? County Median Income Changes and Low Birth Weight Rates Among Births to Black and White Mothers.

Policy Points Policies that increase county income levels, particularly for middle-income households, may reduce low birth weight rates and shrink disparities between Black and White infants. Given the role of aggregate maternal characteristics in predicting low birth weight rates, policies that increase human capital investments (e.g., funding for higher education, job training) could lead to higher income levels while improving population birth outcomes. The association between county income levels and racial disparities in low birth weight is independent of disparities in maternal risks, and thus a broad set of policies aimed at increasing income levels (e.g., income supplements, labor protections) may be warranted. CONTEXT: Low birth weight (LBW; <2,500 grams) and infant mortality rates vary among place and racial group in the United States, with economic resources being a likely fundamental contributor to these disparities. The goals of this study were to examine time-varying county median income as a predictor of LBW rates and Black-White LBW disparities and to test county prevalence and racial disparities in maternal sociodemographic and health risk factors as mediators. METHODS: Using national birth records for 1992-2014 from the National Center for Health Statistics, a total of approximately 27.4 million singleton births to non-Hispanic Black and White mothers were included. Data were aggregated in three-year county-period observations for 868 US counties meeting eligibility requirements (n = 3,723 observations). Sociodemographic factors included rates of low maternal education, nonmarital childbearing, teenage pregnancy, and advanced-age pregnancy; and health factors included rates of smoking during pregnancy and inadequate prenatal care. Among other covariates, linear models included county and period fixed effects and unemployment, poverty, and income inequality. FINDINGS: An increase of $10,000 in county median income was associated with 0.34 fewer LBW cases per 100 live births and smaller Black-White LBW disparities of 0.58 per 100 births. Time-varying county rates of maternal sociodemographic and health risks mediated the association between median income and LBW, accounting for 65% and 25% of this estimate, respectively, but racial disparities in risk factors did not mediate the income association with Black-White LBW disparities. Similarly, county median income was associated with very low birth weight rates and related Black-White disparities. CONCLUSIONS: Efforts to increase income levels-for example, through investing in human capital, enacting labor union protections, or attracting well-paying employment-have broad potential to influence population reproductive health. Higher income levels may reduce LBW rates and lead to more equitable outcomes between Black and White mothers.