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Neuropsychopharmacology : Official... Oct 2022Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. Understanding the genetic architecture...
Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. Understanding the genetic architecture of this comorbidity could be improved by focusing on intermediate traits that show positive genetic correlation with the disorders. Thus, we aimed to characterize the shared vs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD) -beyond genetic correlation, and boost discovery for jointly-associated loci. Summary statistics for MOOD (a binary measure of the tendency to report frequent mood swings), AC (number of standard drinks over a typical consumption week) and AUD GWASs (Ns > 200,000) were analyzed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD. To do so, we used a newly established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly associated genomic loci, which were mapped to genes and biological functions. MOOD was highly polygenic (10.4k single nucleotide polymorphisms, SNPs, SD = 2k) compared to AC (4.9k SNPs, SD = 0.6k) and AUD (4.3k SNPs, SD = 2k). The polygenic overlap of MOOD and AC was twice that of MOOD and AUD (98% vs. 49%), with opposite genetic correlation (-0.2 vs. 0.23), as confirmed in independent samples. MOOD&AUD associated SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 jointly associated loci, fifteen were novel for MOOD, AC and AUD. MOOD, AC and AUD were also strongly associated at the phenotypic level. Overall, using multilevel polygenic quantification, joint loci discovery and functional annotation methods, we evidenced that the polygenic overlap between MOOD and AC/AUD implicated partly shared biological underpinnings, yet, clearly distinct functional patterns between MOOD&AC and MOOD&AUD, suggesting new mechanisms for the comorbidity of AUD with mood disorders.
Topics: Alcoholism; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide
PubMed: 35953530
DOI: 10.1038/s41386-022-01401-6 -
Trends in Genetics : TIG Nov 2021Accurate genetic prediction of complex traits can facilitate disease screening, improve early intervention, and aid in the development of personalized medicine. Genetic... (Review)
Review
Accurate genetic prediction of complex traits can facilitate disease screening, improve early intervention, and aid in the development of personalized medicine. Genetic prediction of complex traits requires the development of statistical methods that can properly model polygenic architecture and construct a polygenic score (PGS). We present a comprehensive review of 46 methods for PGS construction. We connect the majority of these methods through a multiple linear regression framework which can be instrumental for understanding their prediction performance for traits with distinct genetic architectures. We discuss the practical considerations of PGS analysis as well as challenges and future directions of PGS method development. We hope our review serves as a useful reference both for statistical geneticists who develop PGS methods and for data analysts who perform PGS analysis.
Topics: Genome-Wide Association Study; Multifactorial Inheritance; Phenotype
PubMed: 34243982
DOI: 10.1016/j.tig.2021.06.004 -
G3 (Bethesda, Md.) Aug 2023Large-effect loci-those statistically significant loci discovered by genome-wide association studies or linkage mapping-associated with key traits segregate amidst a...
Large-effect loci-those statistically significant loci discovered by genome-wide association studies or linkage mapping-associated with key traits segregate amidst a background of minor, often undetectable, genetic effects in wild and domesticated plants and animals. Accurately attributing mean differences and variance explained to the correct components in the linear mixed model analysis is vital for selecting superior progeny and parents in plant and animal breeding, gene therapy, and medical genetics in humans. Marker-assisted prediction and its successor, genomic prediction, have many advantages for selecting superior individuals and understanding disease risk. However, these two approaches are less often integrated to study complex traits with different genetic architectures. This simulation study demonstrates that the average semivariance can be applied to models incorporating Mendelian, oligogenic, and polygenic terms simultaneously and yields accurate estimates of the variance explained for all relevant variables. Our previous research focused on large-effect loci and polygenic variance separately. This work aims to synthesize and expand the average semivariance framework to various genetic architectures and the corresponding mixed models. This framework independently accounts for the effects of large-effect loci and the polygenic genetic background and is universally applicable to genetics studies in humans, plants, animals, and microbes.
Topics: Humans; Animals; Multifactorial Inheritance; Genome-Wide Association Study; Chromosome Mapping; Genome; Phenotype; Models, Genetic; Polymorphism, Single Nucleotide
PubMed: 37405459
DOI: 10.1093/g3journal/jkad148 -
Behavior Genetics Mar 2023A century after the first twin and adoption studies of behavior in the 1920s, this review looks back on the journey and celebrates milestones in behavioral genetic... (Review)
Review
A century after the first twin and adoption studies of behavior in the 1920s, this review looks back on the journey and celebrates milestones in behavioral genetic research. After a whistle-stop tour of early quantitative genetic research and the parallel journey of molecular genetics, the travelogue focuses on the last fifty years. Just as quantitative genetic discoveries were beginning to slow down in the 1990s, molecular genetics made it possible to assess DNA variation directly. From a rocky start with candidate gene association research, by 2005 the technological advance of DNA microarrays enabled genome-wide association studies, which have successfully identified some of the DNA variants that contribute to the ubiquitous heritability of behavioral traits. The ability to aggregate the effects of thousands of DNA variants in polygenic scores has created a DNA revolution in the behavioral sciences by making it possible to use DNA to predict individual differences in behavior from early in life.
Topics: Genome-Wide Association Study; Genetics, Behavioral; Phenotype; Oligonucleotide Array Sequence Analysis; Multifactorial Inheritance
PubMed: 36662387
DOI: 10.1007/s10519-023-10132-3 -
American Journal of Human Genetics Dec 2022The genotyping of millions of human samples has made it possible to evaluate variants across the human genome for their possible association with risks for numerous... (Review)
Review
The genotyping of millions of human samples has made it possible to evaluate variants across the human genome for their possible association with risks for numerous diseases and other traits by using genome-wide association studies (GWASs). The associations between phenotype and genotype found in GWASs make possible the construction of polygenic scores (PGSs), which aim to predict a trait or disease outcome in an individual on the basis of their genotype (in the disease case, the term polygenic risk score [PRS] is often used). PGSs have shown promise for studying the biology of complex traits and as a tool for evaluating individual disease risks in clinical settings. Although the quantity and quality of data to compute PGSs are increasing, challenges remain in the technical aspects of developing PGSs and in the ethical and social issues that might arise from their use. This ASHG Guidance emphasizes three major themes for researchers working with or interested in the application of PGSs in their own research: (1) developing diverse research cohorts; (2) fostering robustness in the development, application, and interpretation of PGSs; and (3) improving the communication of PGS results and their implications to broad audiences.
Topics: Humans; Multifactorial Inheritance; Genome-Wide Association Study; Genetic Research; Genotype; Phenotype
PubMed: 36459976
DOI: 10.1016/j.ajhg.2022.10.012 -
PLoS Genetics Jul 2022Genetic influences on body mass index (BMI) appear to markedly differ across life, yet existing research is equivocal and limited by a paucity of life course data. We...
Genetic influences on body mass index (BMI) appear to markedly differ across life, yet existing research is equivocal and limited by a paucity of life course data. We thus used a birth cohort study to investigate differences in association and explained variance in polygenic risk for high BMI across infancy to old age (2-69 years). A secondary aim was to investigate how the association between BMI and a key purported environmental determinant (childhood socioeconomic position) differed across life, and whether this operated independently and/or multiplicatively of genetic influences. Data were from up to 2677 participants in the MRC National Survey of Health and Development, with measured BMI at 12 timepoints from 2-69 years. We used multiple polygenic indices from GWAS of adult and childhood BMI, and investigated their associations with BMI at each age. For polygenic liability to higher adult BMI, the trajectories of effect size (β) and explained variance (R2) diverged: explained variance peaked in early adulthood and plateaued thereafter, while absolute effect sizes increased throughout adulthood. For polygenic liability to higher childhood BMI, explained variance was largest in adolescence and early adulthood; effect sizes were marginally smaller in absolute terms from adolescence to adulthood. All polygenic indices were related to higher variation in BMI; quantile regression analyses showed that effect sizes were sizably larger at the upper end of the BMI distribution. Socioeconomic and polygenic risk for higher BMI across life appear to operate additively; we found little evidence of interaction. Our findings highlight the likely independent influences of polygenic and socioeconomic factors on BMI across life. Despite sizable associations, the BMI variance explained by each plateaued or declined across adulthood while BMI variance itself increased. This is suggestive of the increasing importance of chance ('non-shared') environmental influences on BMI across life.
Topics: Adolescent; Adult; Aged; Body Mass Index; Child; Child, Preschool; Cohort Studies; Follow-Up Studies; Humans; Middle Aged; Multifactorial Inheritance; Risk Factors; Socioeconomic Factors; Young Adult
PubMed: 35834443
DOI: 10.1371/journal.pgen.1010233 -
Neuropsychopharmacology : Official... Jan 2021Depression is a heterogeneous and etiologically complex psychiatric syndrome, not a unitary disease entity, encompassing a broad spectrum of psychopathology arising from... (Review)
Review
Depression is a heterogeneous and etiologically complex psychiatric syndrome, not a unitary disease entity, encompassing a broad spectrum of psychopathology arising from distinct pathophysiological mechanisms. Motivated by a need to advance our understanding of these mechanisms and develop new treatment strategies, there is a renewed interest in investigating the neurobiological basis of heterogeneity in depression and rethinking our approach to diagnosis for research purposes. Large-scale genome-wide association studies have now identified multiple genetic risk variants implicating excitatory neurotransmission and synapse function and underscoring a highly polygenic inheritance pattern that may be another important contributor to heterogeneity in depression. Here, we review various sources of phenotypic heterogeneity and approaches to defining and studying depression subtypes, including symptom-based subtypes and biology-based approaches to decomposing the depression syndrome. We review "dimensional," "categorical," and "hybrid" approaches to parsing phenotypic heterogeneity in depression and defining subtypes using functional neuroimaging. Next, we review recent progress in neuroimaging genetics (correlating neuroimaging patterns of brain function with genetic data) and its potential utility for generating testable hypotheses concerning molecular and circuit-level mechanisms. We discuss how genetic variants and transcriptomic profiles may confer risk for depression by modulating brain structure and function. We conclude by highlighting several promising areas for future research into the neurobiological underpinnings of heterogeneity, including efforts to understand sexually dimorphic mechanisms, the longitudinal dynamics of depressive episodes, and strategies for developing personalized treatments and facilitating clinical decision-making.
Topics: Depression; Depressive Disorder, Major; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Neuroimaging
PubMed: 32781460
DOI: 10.1038/s41386-020-00789-3 -
Nature Genetics Dec 2023Biobanks often contain several phenotypes relevant to diseases such as major depressive disorder (MDD), with partly distinct genetic architectures. Researchers face...
Biobanks often contain several phenotypes relevant to diseases such as major depressive disorder (MDD), with partly distinct genetic architectures. Researchers face complex tradeoffs between shallow (large sample size, low specificity/sensitivity) and deep (small sample size, high specificity/sensitivity) phenotypes, and the optimal choices are often unclear. Here we propose to integrate these phenotypes to combine the benefits of each. We use phenotype imputation to integrate information across hundreds of MDD-relevant phenotypes, which significantly increases genome-wide association study (GWAS) power and polygenic risk score (PRS) prediction accuracy of the deepest available MDD phenotype in UK Biobank, LifetimeMDD. We demonstrate that imputation preserves specificity in its genetic architecture using a novel PRS-based pleiotropy metric. We further find that integration via summary statistics also enhances GWAS power and PRS predictions, but can introduce nonspecific genetic effects depending on input. Our work provides a simple and scalable approach to improve genetic studies in large biobanks by integrating shallow and deep phenotypes.
Topics: Humans; Depressive Disorder, Major; Genetic Predisposition to Disease; Biological Specimen Banks; Genome-Wide Association Study; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide
PubMed: 37985818
DOI: 10.1038/s41588-023-01559-9 -
Nature Communications Aug 2022Schizophrenia is a highly heritable psychiatric disorder characterized by widespread functional and structural brain abnormalities. However, previous association studies...
Schizophrenia is a highly heritable psychiatric disorder characterized by widespread functional and structural brain abnormalities. However, previous association studies between MRI and polygenic risk were mostly ROI-based single modality analyses, rather than identifying brain-based multimodal predictive biomarkers. Based on schizophrenia polygenic risk scores (PRS) from healthy white people within the UK Biobank dataset (N = 22,459), we discovered a robust PRS-associated brain pattern with smaller gray matter volume and decreased functional activation in frontotemporal cortex, which distinguished schizophrenia from controls with >83% accuracy, and predicted cognition and symptoms across 4 independent schizophrenia cohorts. Further multi-disease comparisons demonstrated that these identified frontotemporal alterations were most severe in schizophrenia and schizo-affective patients, milder in bipolar disorder, and indistinguishable from controls in autism, depression and attention-deficit hyperactivity disorder. These findings indicate the potential of the identified PRS-associated multimodal frontotemporal network to serve as a trans-diagnostic gene intermediated brain biomarker specific to schizophrenia.
Topics: Bipolar Disorder; Brain; Genetic Predisposition to Disease; Humans; Magnetic Resonance Imaging; Multifactorial Inheritance; Schizophrenia
PubMed: 35995794
DOI: 10.1038/s41467-022-32513-8 -
American Journal of Human Genetics Dec 2022Family history is the standard indirect measure of inherited susceptibility in clinical care, whereas polygenic risk scores (PRSs) have more recently demonstrated...
Family history is the standard indirect measure of inherited susceptibility in clinical care, whereas polygenic risk scores (PRSs) have more recently demonstrated potential for more directly capturing genetic risk in many diseases. Few studies have systematically compared how these overlap and complement each other across common diseases. Within FinnGen (N = 306,418), we leverage family relationships, up to 50 years of nationwide registries, and genome-wide genotyping to examine the interplay of family history and genome-wide PRSs. We explore the dynamic for three types of family history across 24 common diseases: first- and second-degree family history and parental causes of death. Covering a large proportion of the burden of non-communicable diseases in adults, we show that family history and PRS are independent and not interchangeable measures, but instead provide complementary information on inherited disease susceptibility. The PRSs explained on average 10% of the effect of first-degree family history, and first-degree family history 3% of PRSs, and PRS effects were independent of both early- and late-onset family history. The PRS stratified the risk similarly in individuals with and without family history. In most diseases, including coronary artery disease, glaucoma, and type 2 diabetes, a positive family history with a high PRS was associated with a considerably elevated risk, whereas a low PRS compensated completely for the risk implied by positive family history. This study provides a catalogue of risk estimates for both family history of disease and PRSs and highlights opportunities for a more comprehensive way of assessing inherited disease risk across common diseases.
Topics: Adult; Humans; Genome-Wide Association Study; Diabetes Mellitus, Type 2; Multifactorial Inheritance; Genetic Predisposition to Disease; Medical History Taking; Risk Factors
PubMed: 36347255
DOI: 10.1016/j.ajhg.2022.10.009