Open research questions in Genetic Associations and Epidemiology

What the literature leaves open

• The growing comorbidity of type 2 diabetes and colorectal cancer presents a significant public health burden. There is a need to investigate the association between genetic risk and disease status.

  Polygenic risk scores, adiposity, and disease transition in type 2 diabetes and colorectal cancer comorbidity: a population-based Chinese cohort study · 2026 · DOI

• Further research is needed to explore the underlying mechanisms of the sex-specific relationships between MDD and substance use traits. Future studies should consider the role of SES in the associations between MDD and substance use traits. Additional research is required to examine the causal relationships between MDD and substance use traits in different populations.

  Sex differences in the genetic and causal relationships between depression, smoking, and alcohol use: the role of socioeconomic status · 2026 · DOI

• Concerns exist about the representativeness and generalizability of large biobanks for psychiatric genomic research. There is a need to assess the potential impacts of nonrepresentative sampling on the consistency of clinical and genetic aspects of recorded depression.

  Using large biobanks for psychiatric genomic research: Consistency of clinical and genetic aspects of recorded depression across US states in the All of Us Research Program · 2026 · DOI

• Investigate the causal relationships between depression and alcohol use behaviors in other populations, - Examine the role of other factors, such as socioeconomic status and personality traits, in the relationship between depression and alcohol use

  The causal interplay between depression and alcohol use from adolescence to young adulthood: a Mendelian randomization study · 2026 · DOI

• The causal relationships between depression and alcohol use are not well understood. Prior studies have inconsistent findings on the causal relationships between depression and alcohol use. There is a need for a comprehensive investigation of the causal relationships between alcohol use behaviors and depression from adolescence to early adulthood.

  The causal interplay between depression and alcohol use from adolescence to young adulthood: a Mendelian randomization study · 2026 · DOI

• Integrating multi-omics data from different sources and platforms. Identifying causal genes and prioritizing them for further study. Validating dysregulation in different cell types and tissues.

  Integrative multi-omics identifies DOC2A as a novel pharmacological target for bipolar disorder · 2026 · DOI

• Further studies are needed to validate the findings, - Investigation of the molecular mechanisms underlying DOC2A's role in BD is required, - Development of new therapies targeting DOC2A is necessary

  Integrative multi-omics identifies DOC2A as a novel pharmacological target for bipolar disorder · 2026 · DOI

• further investigation of the genetic basis of sex differences in anxiety disorders, - examination of the genetic signals uncovered in this study in independent samples, - analysis of the genetic correlations between anxiety and other mental health disorders

  Unravelling sex differences in the genetic architecture of anxiety · 2026 · DOI

• The extent to which differences in complex traits among human populations are caused by genetic factors is unknown. Prior studies have been limited by confounding from environmental differences. There is a need for a study design that can separate genetic from environmental effects.

  Within-family effect of ancestry on complex traits in a Mexican population · 2026 · DOI

• The shared genetic etiology between dry eye disease and multisite chronic pain remains uncertain. Previous studies have not systematically evaluated the shared genetic basis between the two conditions. There is a need to investigate the genetic correlation between dry eye disease and multisite chronic pain.

  Investigating the shared genetic architecture between dry eye disease and multisite chronic pain · 2026 · DOI

• The limited ability of existing tools to effectively leverage pangenome frameworks for structural variant detection. The increasing challenge of efficient construction of pangenome graphs with the acquisition of larger numbers of samples. The need for improved methods for rare SV discovery, which traditionally relies on large-scale population sequencing data analysis.

  SVPG: a pangenome-based structural variant detection approach and rapid augmentation of pangenome graphs with new samples · 2026 · DOI

• The study acknowledges the potential for unmeasured confounding or reverse causation in observational studies. The study also mentions the need to satisfy core assumptions in Mendelian randomization, such as the relevance assumption, independence assumption, and exclusion restriction. The study notes the potential for heterogeneity and pleiotropy in the results.

  Triangulated evidence provides no support for bidirectional causal pathways between diet/physical activity and depression/anxiety · 2025 · DOI

• Previous studies have presented contradicting insights on the potential causal effects of diet/physical activity on depression/anxiety. There is a need to clarify the relationship between diet/physical activity and depression/anxiety. The study aims to address this gap by using a triangulation framework.

  Triangulated evidence provides no support for bidirectional causal pathways between diet/physical activity and depression/anxiety · 2025 · DOI

• MiXeR is not intended for the identification of specific genes, - Further studies are needed to reveal the underlying shared mechanisms of these traits, - The study only analyzed data from genome-wide association studies (GWAS)

  Polygenic overlap of substance use behaviors and disorders with externalizing and internalizing problems independent of genetic correlations · 2025 · DOI

• Investigate the association between LTCs and anxiety/depression in young people using larger cohorts - Examine the genetic architecture of depression and anxiety across different age-at-onset - Explore the causal relationships between specific LTCs and youth anxiety and depression

  Long-term physical health conditions and youth anxiety and depression: Is there a causal link? · 2025 · DOI

• The observed associations between long-term physical health conditions and youth anxiety and depression may be causal or explained by unmeasured confounding or reverse causation. There is a need to investigate the causal relationship between long-term physical health conditions and youth anxiety and depression.

  Long-term physical health conditions and youth anxiety and depression: Is there a causal link? · 2025 · DOI

• The complexity of the genetic architecture of externalizing and internalizing psychopathology. The need to account for sample overlap and genetic similarity between traits. The challenge of identifying shared genetic liabilities across different traits and spectra.

  Integrating HiTOP and RDoC frameworks Part I: Genetic architecture of externalizing and internalizing psychopathology · 2025 · DOI

• Future studies should investigate the shared and distinct biological mechanisms underlying psychopathology, - Future research should aim to refine psychiatric classification systems and inform treatment approaches, - Future studies should explore the genetic architecture of EXT and INT in more diverse populations, - Future research should investigate the implications of the study's findings for the development of more effective treatments

  Integrating HiTOP and RDoC frameworks Part I: Genetic architecture of externalizing and internalizing psychopathology · 2025 · DOI

• exploring other potential mechanisms, such as brain functional connectivity, - using genetic methods to investigate the relationship between smoking and psychiatric disorders

  The causal effect of smoking on psychiatric disorders: an examination of brain volume as a potential pathway · 2025 · DOI

• There is a lack of clarity regarding the mechanisms that may underlie the relationship between smoking and psychiatric disorders. The causal effect of smoking on psychiatric outcomes is clinically relevant, but the underlying mechanisms are unknown.

  The causal effect of smoking on psychiatric disorders: an examination of brain volume as a potential pathway · 2025 · DOI

• With a total sample size <5,000, it was not feasible to estimate meaningful genetic correlations using LDSC for the DSM-NicDep EAS samples, - The Affymetrix Axiom Exome Array limited our ability to impute

  Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits · 2025 · DOI

• Further research is needed to explore the genetics of nicotine dependence, - Combining diagnostic EHR data with criterion-level analyses of DSM tobacco use disorder may be a promising direction

  Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits · 2025 · DOI

• The study requires a large sample size of individuals with lifetime depression or anxiety. The analysis requires careful consideration of covariates that could act as confounders or explain variance in the phenotypes. The study needs to account for multiple testing when estimating genetic correlations with external phenotypes.

  Genetic overlap between functional impairment and depression and anxiety symptom severity: evidence from the GLAD Study · 2025 · DOI

• limiting generalizability due to focus on European ancestry youth in most SCZ-PRS studies, - results remained consistent when SCZ-PRS and SCZ-FH were jointly modeled but some SCZ-FH associations weakened when income-to-needs was accounted for

  Independent versus joint effects of polygenic or family-based schizophrenia risk in diverse ancestry youth in the ABCD study · 2025 · DOI

• investigating SCZ-related signs and symptoms at earlier time points, - exploring the relationship between SCZ-FH and SCZ-PRS in more diverse populations

  Independent versus joint effects of polygenic or family-based schizophrenia risk in diverse ancestry youth in the ABCD study · 2025 · DOI

Most-cited papers in Genetic Associations and Epidemiology

• The UK Biobank resource with deep phenotyping and genomic data · Nature · 2018 · 9,211 citations
• Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls · Nature · 2007 · 7,947 citations
• Finding the missing heritability of complex diseases · Nature · 2009 · 7,029 citations
• The GTEx Consortium atlas of genetic regulatory effects across human tissues · Science · 2020 · 5,140 citations
• The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans · Science · 2015 · 4,879 citations
• The Structure of Haplotype Blocks in the Human Genome · Science · 2002 · 4,761 citations
• A haplotype map of the human genome · Nature · 2005 · 4,707 citations
• The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions · American Journal of Psychiatry · 2003 · 4,483 citations
• Genetic effects on gene expression across human tissues · Nature · 2017 · 4,183 citations
• The Future of Genetic Studies of Complex Human Diseases · Science · 1996 · 3,945 citations

Most recent work

• Genetic association data are broadly consistent with stabilizing selection shaping human common diseases and traits · bioRxiv · 2026
• Chinese Immune Multi-Omics Atlas · Science · 2026
• Heritable confounding of exposure and outcome in Mendelian randomization studies · medRxiv · 2026
• Imputation of structural variants using a multi-ancestry long-read sequencing panel enables identification of disease associations · medRxiv · 2026
• One score to rule them all: regularized ensemble polygenic risk prediction with GWAS summary statistics · bioRxiv · 2026
• Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome · Cell · 2026
• Polygenic risk scores are not genetic predispositions · Nature Human Behaviour · 2026
• Benchmarking methods integrating GWAS and single-cell transcriptomic data for mapping trait-cell type associations · medRxiv · 2026
• From polygenic risk to digital twins: the future of personalised cardiovascular medicine · Frontiers in Cardiovascular Medicine · 2026
• Clinical genetic variation across Hispanic populations in the Mexican Biobank · Nature Medicine · 2026

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