Showing papers by "Laura J. Scott published in 2021"

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

The trans-ancestral genomic architecture of glycemic traits

Abstract: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study

Abstract: Importance Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. Objective To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression. Design, Setting, and Participants Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021. Exposures Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts. Main Outcomes and Measures Depression status was defined based on health records and self-report questionnaires. Results There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = −0.018, SE = 0.003,P = 4.43x10−8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005,P = 6.48x10−9for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = −0.003, SE = 0.005,P = .53 for rs4656484 and β = −0.005, SE = 0.004,P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression wasr = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = −0.212, SE = 0.084), contrary to findings for individuals of European descent. Conclusions and Relevance These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.

Exome sequencing in bipolar disorder reveals shared risk gene AKAP11 with schizophrenia

Abstract: Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06, P = 2.83 × 10−9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Abstract: Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Genetic effects on liver chromatin accessibility identify disease regulatory variants.

Abstract: Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci

Cabbage and Sauerkraut Consumption in Adolescence and Adulthood and Breast Cancer Risk among US-Resident Polish Migrant Women

Abstract: Background: Breast cancer (BC) incidence and mortality are lower in Poland than in the United States (US). However, Polish-born migrant women to US approach the higher BC mortality rates of US women. We evaluated the association between consumption of cabbage/sauerkraut foods and BC risk in Polish-born migrants to US. Methods: We conducted a case–control study of BC among Polish-born migrants in Cook County and the Detroit Metropolitan Area. Cases (n = 131) were 20–79 years old with histological/cytological confirmation of invasive BC. Population-based controls (n = 284) were frequency matched to cases on age and residence. Food frequency questionnaires assessed diet during adulthood and age 12–13 years. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated with conditional logistic regression. Consumption of total, raw/short-cooked, and long-cooked cabbage/sauerkraut foods was categorized as low, medium, or high (frequency of servings/week). Results: Higher consumption of total and raw/short-cooked cabbage/sauerkraut foods, during both adolescence and adulthood, was associated with a significantly lower BC risk. Consumption of long-cooked cabbage/sauerkraut foods was low and not significantly associated with risk. The multivariate OR for total cabbage/sauerkraut consumption, high vs. low (>4 vs. ≤2 servings/week) during adolescence was 0.36 (95% CI = 0.18–0.71, ptrend 3 vs. ≤1.5 servings/week), the ORs were 0.35 (95% CI = 0.16–0.72, ptrend < 0.01) during adolescence and 0.37 (95% CI = 0.17–0.78, ptrend < 0.01) during adulthood. For joint adolescent/adult consumption of raw/short-cooked cabbage/sauerkraut foods, (high, high) vs. (low, low), the OR was 0.23 (95% CI = 0.07–0.65). The significant association for high adolescent consumption of raw/short-cooked cabbage/sauerkraut foods and reduced BC risk was consistent across all levels of consumption in adulthood. Conclusion: Greater consumption of total and raw/short-cooked cabbage/sauerkraut foods either during adolescence or adulthood was associated with significantly reduced BC risk among Polish migrant women. These findings contribute to the growing literature suggesting a protective effect of a potentially modifiable factor, cruciferous vegetable intake, on breast cancer risk.

Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Abstract: Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN ( Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.

A powerful subset-based method identifies gene set associations and improves interpretation in UK Biobank.

Abstract: Tests of association between a phenotype and a set of genes in a biological pathway can provide insights into the genetic architecture of complex phenotypes beyond those obtained from single-variant or single-gene association analysis. However, most existing gene set tests have limited power to detect gene set-phenotype association when a small fraction of the genes are associated with the phenotype and cannot identify the potentially "active" genes that might drive a gene set-based association. To address these issues, we have developed Gene set analysis Association Using Sparse Signals (GAUSS), a method for gene set association analysis that requires only GWAS summary statistics. For each significantly associated gene set, GAUSS identifies the subset of genes that have the maximal evidence of association and can best account for the gene set association. Using pre-computed correlation structure among test statistics from a reference panel, our p value calculation is substantially faster than other permutation- or simulation-based approaches. In simulations with varying proportions of causal genes, we find that GAUSS effectively controls type 1 error rate and has greater power than several existing methods, particularly when a small proportion of genes account for the gene set signal. Using GAUSS, we analyzed UK Biobank GWAS summary statistics for 10,679 gene sets and 1,403 binary phenotypes. We found that GAUSS is scalable and identified 13,466 phenotype and gene set association pairs. Within these gene sets, we identify an average of 17.2 (max = 405) genes that underlie these gene set associations.

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Abstract: Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

Genome-wide association study of 1,391 plasma metabolites in 6,136 Finnish men identifies 303 novel signals and provides biological insights into human diseases

Abstract: Few studies have explored the impact of rare variants (minor allele frequency, MAF