Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among ...study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.
With increasing representation of global populations in genetic studies, there is an opportunity for advanced methods development and a need for consensus “best practices” for analyzing datasets. We provide background on the scientific and ethical importance of including underrepresented groups in genetics research and offer guidance for genome-wide analysis of ancestrally diverse study cohorts.
Peripartum depression (PD) is a common mood disorder associated with negative outcomes for mother and child. PD is an understudied disorder in psychiatric genetics, and progress characterizing its ...genetic architecture has been limited by a lack of disorder-specific research, heterogeneous and evolving phenotypic definitions, inadequate representation of global populations, low-powered studies, and insufficient data amenable to large meta-analyses. The increasing availability of large-scale, population-level efforts, like biobanks, have the potential to accelerate scientific discovery and translational research by leveraging clinical, molecular, and self-report data from hundreds of thousands of individuals. Although these efforts will not fully equip researchers to confront every challenge posed by systemic issues in data collection, such as the reliance on minimal phenotyping strategies, the field is in a position to learn from other successful psychiatric genetic investigations. This review summarizes the current state of PD genetics research and highlights research challenges, including the impact of phenotype depth, measurement, and definition on the replicability and interpretability of genomic research. Recommendations for advancing health equity and improving the collection, analysis, discussion, and reporting of measures for PD research are provided.
Variation in genes involved in ethanol metabolism has been shown to influence risk for alcohol dependence (AD) including protective loss of function alleles in ethanol metabolizing genes. We ...therefore hypothesized that people with severe AD would exhibit different patterns of rare functional variation in genes with strong prior evidence for influencing ethanol metabolism and response when compared to genes not meeting these criteria.
Leverage a novel case only design and Whole Exome Sequencing (WES) of severe AD cases from the island of Ireland to quantify differences in functional variation between genes associated with ethanol metabolism and/or response and their matched control genes.
First, three sets of ethanol related genes were identified including those a) involved in alcohol metabolism in humans b) showing altered expression in mouse brain after alcohol exposure, and altering ethanol behavioral responses in invertebrate models. These genes of interest (GOI) sets were matched to control gene sets using multivariate hierarchical clustering of gene-level summary features from gnomAD. Using WES data from 190 individuals with severe AD, GOI were compared to matched control genes using logistic regression to detect aggregate differences in abundance of loss of function, missense, and synonymous variants, respectively.
Three non-independent sets of 10, 117, and 359 genes were queried against control gene sets of 139, 1522, and 3360 matched genes, respectively. Significant differences were not detected in the number of functional variants in the primary set of ethanol-metabolizing genes. In both the mouse expression and invertebrate sets, we observed an increased number of synonymous variants in GOI over matched control genes. Post-hoc simulations showed the estimated effects sizes observed are unlikely to be under-estimated.
The proposed method demonstrates a computationally viable and statistically appropriate approach for genetic analysis of case-only data for hypothesized gene sets supported by empirical evidence.
Neuropsychiatric and substance use disorders (NPSUDs) have a complex etiology that includes environmental and polygenic risk factors with significant cross-trait genetic correlations. Genome-wide ...association studies (GWAS) of NPSUDs yield numerous association signals. However, for most of these regions, we do not yet have a firm understanding of either the specific risk variants or the effects of these variants. Post-GWAS methods allow researchers to use GWAS summary statistics and molecular mediators (transcript, protein, and methylation abundances) infer the effect of these mediators on risk for disorders. One group of post-GWAS approaches is commonly referred to as transcriptome/proteome/methylome-wide association studies, which are abbreviated as T/P/MWAS (or collectively as XWAS). Since these approaches use biological mediators, the multiple testing burden is reduced to the number of genes (∼20,000) instead of millions of GWAS SNPs, which leads to increased signal detection. In this work, our aim is to uncover likely risk genes for NPSUDs by performing XWAS analyses in two tissues-blood and brain. First, to identify putative causal risk genes, we performed an XWAS using the Summary-data-based Mendelian randomization, which uses GWAS summary statistics, reference xQTL data, and a reference LD panel. Second, given the large comorbidities among NPSUDs and the shared cis-xQTLs between blood and the brain, we improved XWAS signal detection for underpowered analyses by performing joint concordance analyses between XWAS results i) across the two tissues and ii) across NPSUDs. All XWAS signals i) were adjusted for heterogeneity in dependent instruments (HEIDI) (non-causality)
-values and ii) used to test for pathway enrichment. The results suggest that there were widely shared gene/protein signals within the major histocompatibility complex region on chromosome 6 (
and
) and elsewhere in the genome (
and
). The identification of putative molecular genes and pathways underlying risk may offer new targets for therapeutic development. Our study revealed an enrichment of XWAS signals in vitamin D and omega-3 gene sets. So, including vitamin D and omega-3 in treatment plans may have a modest but beneficial effect on patients with bipolar disorder.
Background
Drinking motives are robust proximal predictors of alcohol use behaviors and may mediate distinct etiological pathways in the development of alcohol misuse. However, little is known about ...the genetic and environmental etiology of drinking motives themselves and their potential utility as endophenotypes.
Methods
Here, we leverage a longitudinal study of college students from diverse racial/ethnic backgrounds (phenotypic N = 9889, genotypic N = 4855) to investigate the temporal stability and demographic and environmental predictors of four types of drinking motives (enhancement, social, coping, and conformity). Using genome‐wide association study (GWAS) and in silico tools, we characterize their associated genes and genetic variants (single nucleotide polymorphisms or SNPs).
Results
Drinking motives were stable across four years of college (ICC >0.74). Some robust environmental predictors of alcohol misuse (parental autonomy granting and peer deviance) were broadly associated with multiple types of drinking motives, while others (e.g., trauma exposure) were type specific. Genome‐wide analyses indicated modest SNP‐based heritability (14–22%, n.s.) and several suggestive genomic loci that corroborate findings from previous molecular genetic studies (e.g., PECR and SIRT4 genes), indicating possible differences in the genetic etiology of positive versus negative reinforcement drinking motives that align with an internalizing/externalizing typology of alcohol misuse. Coping motives were significantly genetically correlated with alcohol use disorder diagnoses (rg = 0.71, p = 0.001). However, results from the genetic analyses were largely underpowered to detect significant associations.
Conclusions
Drinking motives show promise as endophenotypes but require further investigation in larger samples to further our understanding of the etiology of alcohol misuse.
We investigated drinking motives as possible endophenotypes for alcohol misuse in a longitudinal sample of college students. Motives were stable across college and robustly associated with environmental factors like trauma, peer deviance, and parenting. Suggestive genomic association signals and a genetic correlation between coping motives and alcohol use disorder indicates their potential for use as endophenotypes. Drinking motives are relatively simple measures to collect and may benefit from inclusion in larger samples and biobanks.
Little is known about how non-suicidal and suicidal self-injury are differentially genetically related to psychopathology and related measures. This research was conducted using the UK Biobank ...Resource, in participants of European ancestry (N = 2320 non-suicidal self-injury NSSI only; N = 2648 suicide attempt; 69.18% female). We compared polygenic scores (PGS) for psychopathology and other relevant measures within self-injuring individuals. Logistic regressions and likelihood ratio tests (LRT) were used to identify PGS that were differentially associated with these outcomes. In a multivariable model, PGS for anorexia nervosa (odds ratio OR = 1.07; 95% confidence intervals CI 1.01; 1.15) and suicidal behavior (OR = 1.06; 95% CI 1.00; 1.12) both differentiated between NSSI and suicide attempt, while the PGS for other phenotypes did not. The LRT between the multivariable and base models was significant (Chi square = 11.38, df = 2, p = 0.003), and the multivariable model explained a larger proportion of variance (Nagelkerke's pseudo-R
= 0.028 vs. 0.025). While NSSI and suicidal behavior are similarly genetically related to a range of mental health and related outcomes, genetic liability to anorexia nervosa and suicidal behavior is higher among those reporting a suicide attempt than those reporting NSSI-only. Further elucidation of these distinctions is necessary, which will require a nuanced assessment of suicidal versus non-suicidal self-injury in large samples.
The availability of large-scale biobanks linking genetic data, rich phenotypes, and biological measures is a powerful opportunity for scientific discovery. However, real-world collections frequently ...have extensive missingness. While missing data prediction is possible, performance is significantly impaired by block-wise missingness inherent to many biobanks.
To address this, we developed Missingness Adapted Group-wise Informed Clustered (MAGIC)-LASSO which performs hierarchical clustering of variables based on missingness followed by sequential Group LASSO within clusters. Variables are pre-filtered for missingness and balance between training and target sets with final models built using stepwise inclusion of features ranked by completeness. This research has been conducted using the UK Biobank (
> 500 k) to predict unmeasured Alcohol Use Disorders Identification Test (AUDIT) scores.
The phenotypic correlation between measured and predicted total score was 0.67 while genetic correlations between independent subjects was high >0.86.
Phenotypic and genetic correlations in real data application, as well as simulations, demonstrate the method has significant accuracy and utility for increasing power for genetic loci discovery.
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