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PubMed1981

Age-of-onset and genetic transmission in affective disorders.

Age-of-onset data were gathered on first-degree relatives of 252 probands with bipolar and unipolar affective disorders. Early onset probands (younger than 40 at onset) had more early onset relatives and a greater risk for affective disorder among their relatives than late onset probands (40 or older). This indicates that age-of-onset is a familial factor correlated with the liability to affective illness. Multiple threshold models of inheritance were applied to the data using age-of-onset as a liability-threshold determinant. The hypothesis of autosomal single-major locus was ruled out. Multifactorial-polygenic inheritance provided a better fit to the data. The data suggest that early and late onset affective disorders can be placed at different thresholds on a genetic environmental continuum and that the early onset form is more deviant genetically than the late onset type. The implications for genetic research in affective disorder are discussed.

Affective Disorders, Psychotic↗

PubMed1981

Application of the major gene index and offspring-between-parents function to dermatoglyphic fingertip variables.

Forty-eight digital dermatoglyphic variables in 192 nuclear families were analyzed to search for evidence of major gene effects, utilizing a pair of recently developed statistics called the major gene index (MGI) and offspring-between-parents (OBP) function. They operate on the principle that under a multifactorial blending inheritance scheme an offspring's phenotypic value approximates the midparental value, whereas under major gene inheritance, the child's value more closely resembles that of one of his parents. Both statistics yielded comparable results. All ridge-count variables showed no strong deviation from a multifactorial model. Pattern-type variables gave values suggesting the presence of major gene effects, but these results were probably the consequence of the variables' relatively discrete distributions, since a departure of a variable from a reasonably continuous phenotypic distribution was shown to interfere significantly with the interpretation of both statistics.

Chromosome Mapping↗

PubMed1982

Genetic models of schizophrenia.

Multiple threshold models of inheritance are applied to a large sample of Franz Kallmann's (1938) pedigree data on schizophrenia. Paranoid and nonparanoid subtypes are represented in the models at different thresholds on a continuum of genetic-environmental liability. Single major locus and multifactorial-polygenic inheritance are ruled out as modes of transmission. These findings suggest that the paranoid-non-paranoid dichotomy cannot be used as a genetic threshold determinant in the population studied.

Gene Frequency↗

PubMed1986

Cleft lip with or without cleft palate: reanalysis of a three-generation family study from England.

The study population consists of 424 three-generation families originally ascertained through nonsyndromic cleft lip with or without cleft palate (CL +/- P) surgical probands by Carter et al [J Med Genet 19:246-261, 1982] in London, England. Carter et al proposed that the multifactorial threshold model (MF/T) could explain the data. The goal of our study was to test that hypothesis, plus alternatives, rigorously. Two approaches were used: 1) Carter et al had proposed that these data were consistent with the predictions of the MF/T as presented by Carter [Br Med Bull 25:52-57, 1969]. However, we tested those predictions using standard chi 2 tests and found statistically significant departures from the predictions in these families. 2) Complex segregation analysis under the mixed model was performed. Again, the MF/T model could be rejected, as could a model of a major locus alone. The best-fitting model included both major locus and multifactorial components. When the data were analyzed in two parts based on the proband's phenotype (CL vs CL + P) there was some evidence of heterogeneity in that there was a significant proportion of sporadic cases in the families of CL probands but not in the families of CL + P probands. Our results provide no support for the MF/T model. The results from segregation analyses of CL +/- P in these families were most consistent with autosomal major gene inheritance plus multifactorial contributions.

Cleft Lip↗

PubMed1989

[Heredity and diseases of the organs of the urinary system: results and prospects of research].

The paper deals with current ideas of the role played by heredity in the development of diseases of the urinary system organs (USO). Hereditary nephropathies are divided into groups of disorders associated with chromosome aberrations (0.28 percent), monogen-inherited pathology (13 percent), multifactorial or polygen-inherited pathology (86.72 percent). Hereditary predisposition associated with antigenic determinants of the HIA system, immune, metabolic, histological defects and other factors are implicated in the development of multifactorial diseases. The pathways by which the disease predisposition is realized are nonuniform. There prospect well novel biotechnological approaches, virologic, pharmacogenetic studies aimed at understanding of the role of heredity in the development of USO disorders, at diagnosing borderline illnesses, and at preventing the disease manifestations.

Child↗

PubMed2025

Polygenic Prediction of Peripheral Artery Disease and Major Adverse Limb Events.

IMPORTANCE: Peripheral artery disease (PAD) is a heritable atherosclerotic condition associated with functional decline and high risk for limb loss. With growing knowledge of the genetic basis for PAD and related risk factors, there is potential opportunity to identify individuals at high risk using polygenic risk scores (PRSs). OBJECTIVE: To develop a novel integrated, multiancestry polygenic score for PAD (PRS-PAD) and evaluate its risk estimation for PAD and major adverse limb events in 3 populations. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study was conducted among individuals with genotyping and electronic health record data in the UK Biobank (2006-2021), All of Us (AoU, 2018-2022), and the Mass General Brigham Biobank (MGBB, 2010-2023). Data were analyzed from July 2023 to February 2025. EXPOSURES: PRS-PAD, previously published PAD polygenic scores, and clinical risk factors. MAIN OUTCOMES AND MEASURES: The primary outcomes were PAD and major adverse limb events, defined as a surrogate of major amputation and acute limb ischemia. RESULTS: The study populations included 400 533 individuals from the UK Biobank (median [IQR] age, 58.2 [45.0-71.4] years; 216 215 female participants [53.9%]), 218 500 from AoU (median [IQR] age, 53.6 [37.7-65.0] years; 132 647 female participants [60.7%]), and 32 982 from MGBB (median [IQR] age, 56.0 [32.0-80.0] years; 18 277 female participants [55.4%]). In the UK Biobank validation cohort, PRS-PAD was associated with an odds ratio [OR] per SD increase of 1.63 (95% CI, 1.60-1.68; P < .001). After adjusting for clinical risk factors, the OR for the top 20% of PRS-PAD was 1.68 (95% CI, 1.62-1.74; P < .001) compared to the remainder of the population. Among PAD cases without a history of diabetes, smoking, or chronic kidney disease (n = 3645), 1097 individuals (30.1%) had a high PRS-PAD (top 20%). In incident disease analysis, PRS-PAD improved discrimination (C statistic, 0.761), which was nearly equivalent to the performances of diabetes (C statistic, 0.760) and smoking (C statistic, 0.765). Among individuals with prevalent PAD, high PRS-PAD was associated with an increased risk of incident major adverse limb events in the UK Biobank (hazard ratio [HR], 1.75; 95% CI, 1.18-2.57; P = .005), MGBB (HR, 1.56; 95% CI, 1.06-2.30; P = .02), and AoU (HR, 1.57; 95% CI, 1.06-2.33; P = .03). CONCLUSIONS AND RELEVANCE: This cohort study develops a new PRS that stratifies risk of PAD and adverse limb outcomes. Incorporating polygenic risk into PAD care warrants further investigation to guide screening and tailor management to prevent major adverse limb events.

Humans↗

PubMed2025

Polygenic Susceptibility in Peripartum, Alcohol-Induced, and Cancer Therapy-Related Cardiomyopathies.

IMPORTANCE: Rare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) cardiomyopathies. However, it remains unclear whether a polygenic predisposition to DCM also contributes to these conditions. OBJECTIVE: To assess the association of a DCM polygenic score with PPCM, ACM, and CCM, and to evaluate the contributions of monogenic and polygenic susceptibilities to these secondary cardiomyopathies. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective genetic association analysis of data from the Mass General Brigham (MGB) Biobank (n = 42 137, 2008-2025), with replication in the UK Biobank (n = 295 160, 2005-2010), FinnGen (n = 417 950, 2017-2025), and the Veterans Affairs Million Veteran Program (n = 516 066, 2011-2025). In MGB Biobank, medical records were reviewed to ascertain secondary cardiomyopathy cases and antecedent clinical risk factors. EXPOSURES: DCM polygenic risk score and DCM monogenic variants. MAIN OUTCOMES AND MEASURES: The primary outcomes were the association of the DCM polygenic risk score with PPCM, ACM, and CCM and the prevalence of monogenic variants and a high polygenic score among individuals with cardiomyopathy. RESULTS: The mean (SD) age in the MGB Biobank was 55.7 (17.0) years at enrollment, and 24 551 (58.3%) were female. Across the 4 study cohorts, 3414 individuals with secondary cardiomyopathy were identified, including 70 with PPCM, 2281 with ACM, and 1063 with CCM. The DCM polygenic score was associated with PPCM (odds ratio [OR], 1.82 per SD; 95% CI, 1.43-2.30), ACM (OR, 1.56; 95% CI,1.34-1.82), and CCM (OR, 1.64; 95% CI,1.24-2.15) (all with P < .001). Monogenic variants were enriched but present in 7 of 113 individuals with medical record-reviewed cardiomyopathy in MGB, while 66 had a high polygenic score, which conferred an approximately 3-fold increased odds of cardiomyopathy. Most individuals with cardiomyopathy lacked antecedent clinical risk factors. CONCLUSIONS AND RELEVANCE: In this cohort study, individuals with PPCM, ACM, and CCM were enriched for monogenic DCM variants and a high DCM polygenic score, suggesting a shared genetic susceptibility influenced by distinct environmental precipitants. These findings support a shared genetic architecture between secondary cardiomyopathies and DCM, although additional work with larger numbers of individuals with cardiomyopathy is needed to confirm these findings.

Humans↗

PubMed2025

Polygenic Contributions to Lithium Augmentation Outcomes in Unipolar Depression.

IMPORTANCE: Lithium augmentation is an effective treatment for patients with major depression after inadequate antidepressant response, but therapeutic outcomes vary considerably between individuals. Molecular studies may provide novel insights into treatment prediction and guide personalized therapy. OBJECTIVE: To investigate the association of polygenic risk scores (PRS) for schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) with clinical outcomes after lithium augmentation. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed prospectively assessed treatment outcomes in patients who underwent lithium augmentation. Disorder-specific PRS were calculated using well-powered genome-wide association study summary statistics. Participants were recruited from 13 psychiatric hospitals, primarily in the greater Berlin area, between 2008 and 2020. They were patients with MDD who showed inadequate response to at least 1 antidepressant, a baseline score of 12 or more on the 17-item Hamilton Depression Rating Scale (HAMD-17), adequate treatment duration (≥4 weeks), and no diagnostic or co-medication changes. Data analysis was conducted between June 2022 and November 2023. EXPOSURE: Polygenic risk scores for MDD, SCZ, or BIP. MAIN OUTCOMES AND MEASURES: Response was defined as a 50% or greater reduction in HAMD-17 score, remission as a HAMD-17 score of 7 or less. Cox proportional hazards models, adjusted for ancestry, demographic, and clinical covariates, were used to estimate hazard ratios (HRs) for favorable outcomes. RESULTS: Among 193 patients (mean [SD] age, 49.5 [13.4] years; 118 [61.1%] female and 75 [38.9%] male), higher BIP-PRS were associated with both response (HR, 1.29; 95% CI, 1.02-1.63; P = .03) and remission (HR, 1.52; 95% CI, 1.14-2.04; P = .004), explaining 2.51% and 4.53% of the variability in treatment outcomes, respectively. Individuals in the highest tertile of the BIP-PRS distribution had a 2.02-fold (95% CI, 1.15-3.53) higher likelihood of response and a 2.26-fold (95% CI, 1.17-4.36) higher chance of remission compared with those in the lowest tertile. Additionally, lower MDD-PRS was associated with better response to lithium augmentation (HR, 0.81; 95% CI, 0.66-1.00; P = .048; Nagelkerke R2 = 1.99%). No significant associations were observed between SCZ-PRS and response (HR, 1.00; 95% CI, 0.80-1.24; P = .97) or remission (HR, 1.12; 95% CI, 0.85-1.48; P = .42). CONCLUSIONS AND RELEVANCE: Individuals carrying a higher polygenic burden for BIP and lower polygenic risk for MDD are more likely to benefit from lithium augmentation. Our findings suggest that disease-related PRS may aid in developing treatment prediction models for lithium augmentation response in depression, potentially informing clinical decision-making.

Humans↗

PubMed2024

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis.

OBJECTIVE: Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS. METHODS: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression. RESULTS: A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. INTERPRETATION: Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Humans↗

PubMed1992

Familial intestinal malrotation with midgut volvulus and facial anomalies: a disorder involving a gene controlling the normal gut rotation?

We report on 2 sisters with congenital midgut volvulus. Both had similar facial changes different from those of their parents and the other 2 unaffected sibs. Both parents had normal barium meal roentgenograms. The occurrence of these abnormalities in sibs born to parents with apparently normal gastrointestinal tract anatomy suggest autosomal recessive inheritance, although a coincidence, multifactorial or autosomal dominant inheritance with nonpenetrance in either of the parents cannot be excluded.

Abnormalities, Multiple↗

PubMed2026

Shared genetic architecture between DTI-ALPS traits and neurodegenerative diseases.

INTRODUCTION: Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index is associated with neurodegenerative diseases (NDDs), but its shared genetic basis with NDDs remains unclear. METHODS: By integrating genome-wide association datasets for three DTI-ALPS traits and seven NDDs, we quantified polygenic overlap using MiXeR, identified shared loci using conditional and conjunctional false discovery rate analyses, and performed gene mapping, enrichment, temporal expression, and transcriptome-wide association analyses. RESULTS: DTI-ALPS traits showed widespread but heterogeneous polygenic overlap with NDDs. We identified 22 shared loci, including novel associations implicating GAK and SIAH3, with the strongest convergence at 17q21.31. Shared loci mapped to 183 protein-coding genes enriched in the endolysosomal system and microtubule cytoskeleton. These genes showed similar temporal expression patterns, and 45 were associated with both DTI-ALPS traits and NDDs. DISCUSSION: These findings reveal a shared genetic architecture between DTI-ALPS traits and NDDs, highlighting mechanisms that may contribute to their overlap.

Neurodegenerative Diseases↗

PubMed1995

Frequency and characteristics of familial aggregation of Paget's disease of bone.

The cause of Paget's disease of bone (PDB) is unknown. In an attempt to ascertain the proportion of familial cases and evaluate the influence of genetic factors on the occurrence of the disease, a study was undertaken based on 35 PDB patients from our Unit. Their families were investigated, with the participation of a total of 128 first-degree relatives. Fourteen (40%) of these 35 index cases had at least one other first-degree relative affected with PDB and were defined as "familial." The remaining 21 (60%) were considered "sporadic." The frequency of males in the familial cases (79%) was significantly higher than among the sporadics (29%; p < or = 0.01). Mean age at diagnosis (63.1 +/- 12.6 vs. 71.3 +/- 8.7; p < or = 0.02), proportion of polyostotic cases (85.7% vs. 52.4%, p < or = 0.05), and mean number of involved bones per patient (4.36 +/- 2.50 vs. 2.33 +/- 1.93, p < or = 0.01) differ significantly in the familial and sporadic groups. The disease appears to be transmitted via both paternal and maternal sides, and pedigree analysis suggested an autosomal dominant inheritance or multifactorial mechanism. Apart from green-and-blue eye color, which was clearly associated with familial grouping (OR 6.25, 95% CI 1.15-37.16, p < or = 0.01), crude analysis on several genetically based traits and environmental variables revealed no other significant differences between the groups. The adjusted odds ratio estimated for green-and-blue eye color was 2.92 (95% CI 0.38-22.74).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2025

Protective Effects of Genetic Proxies of Cognitive Reserve in Parkinson's Disease: A Longitudinal Multi-Cohort Study.

BACKGROUND: Resilience factors are crucial in the progression of neurodegenerative diseases. However, it remains unclear whether a genetic predisposition to cognitive reserve influences clinical heterogeneity in the prognosis of Parkinson's disease (PD). OBJECTIVES: The aim is to evaluate the utility of polygenic scores (PGSs) for cognitive reserve proxies, including intelligence (INT), educational attainment (EA), and occupational attainment (OA), in predicting the clinical progression of PD. METHODS: Genetic and clinical data for progression of PD (progression to Hoehn and Yahr stage ≥3, progression to a Montreal Cognitive Assessment score ≤24, and occurrence of psychosis) were obtained from the Accelerating Medicine Partnership Parkinson's Disease database. We conducted multivariate Cox regression analysis, adjusting for relevant covariates, including years of education, variants in APOE, GBA1, LRRK2, and other cognitive reserve-related PGSs. RESULTS: All cognitive reserve-related PGSs significantly reduced the risk of cognitive decline, and EA-PGS (hazard ratio [HR], 0.550; 95% confidence interval [CI], 0.447-0.676; P < 0.001) remained significant after controlling for INT-PGS and OA-PGS. EA-PGS (HR, 0.805; 95% CI, 0.672-0.964; P = 0.019) was significantly associated with better motor prognosis after controlling for other PGSs. OA-PGS was linked to a decreased risk of developing psychosis in PD and remained significant after adjusting for others (HR, 0.784; 95% CI, 0.631-0.975; P = 0.029). CONCLUSIONS: Genetic proxies of cognitive reserve are associated with a reduced risk of cognitive decline, motor progression, and development of psychosis in PD. These findings may enhance our understanding of individual differences in resilience in progression of PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Humans↗

PubMed1983

Family study of congenital limb reduction abnormalities in Hungary 1975-1977.

A family study of 274 index patients with limb reduction malformations born in Hungary from 1975 to 1977 is reported. The majority of 789 first-degree relatives were personally examined. Information was collected on 1094 uncles and aunts and on 1095 cousins, and those affected by limb malformations were examined. Among 789 first-degree relatives six were affected by a similar malformation (radial, ulnar and central ray defects) and 1 by a malformation of a different type; no secondary cases of the same type were found among the relatives of patients with terminal transverse and amniogenic malformations, and with limb malformations which were part of syndromes or unclassifiable associations with other malformations. While a few rare types of limb defects are due to dominant genes, the aetiology of most cases is obscure. There is no evidence of sex-linked inheritance, of multifactorial causation or of environmental factors shared by relatives. These results are similar to those of an earlier study by Birch-Jensen.

Abnormalities, Multiple↗

PubMed2026

Advancing genetic evaluation of milk yield and composition using a genomic-polygenic model in smallholder dairy cattle farms in Thailand.

Improving the accuracy of genetic evaluation in smallholder dairy systems is essential for sustainable productivity. However, traditional polygenic models (PM) are often constrained by incomplete pedigree, heterogeneous management, and limited genotyping resources. This study evaluated a genomic-polygenic model (GPM) relative to a PM using data from a multibreed dairy population raised under Thai tropical smallholder conditions. Phenotypic records for 305-day milk yield (MY), fat percentage (FP), protein percentage (PP), and somatic cell count (SCC) from 14,417 first-lactation cows across 1,321 farms were analyzed together with genotypes from 5,479 animals generated using GeneSeek Genomic Profiler (GGP) arrays ranging from 9 K to 150 K SNPs. Both models included herd-year-season of calving, age at first calving, and heterosis as fixed effects, and additive genetic and residual components treated as random. The GPM yielded higher additive genetic variances and heritability estimates and produced more biologically consistent antagonistic correlations among traits than the PM. Prediction accuracy was improved for all animal groups under the GPM, with the largest gain observed in genotyped young sires (18.36%). Pedigree connectedness analysis indicated that genotyping animals with low to moderate relationships enhances accuracy cost-effectively. Despite persistent challenges associated with heterogeneous management and limited pedigree depth, the results demonstrate the practical value of genomic-polygenic evaluation for smallholder multibreed dairy populations in tropical environments.

Animals↗

PubMed2026

Advancements in the Understanding of the Genetics of Obsessive-Compulsive Disorder (OCD).

PURPOSE OF REVIEW: This review summarizes recent advances in the genetics of Obsessive-Compulsive Disorder (OCD), their contribution to understanding disorder biology, and implication for clinical translation. RECENT FINDINGS: Recent GWAS identified 30 genome-wide significant loci and prioritized 25 putatively causal genes. Rare variant studies implicated specific genes, including CHD8, CELSR3, SLITRK5, and QRICH1. Evidence from common and rare variants support brain- and immune-related pathways. Genetic overlap with obsessive compulsive symptoms and other psychiatric disorders indicate shared underlying biology. Current evidence is largely based on individuals of European ancestry, although global efforts are underway to improve ancestral diversity in OCD genetics. Given the urgent need for improved treatment, genetically informed clinical translation approaches hold promise, including pharmacogenetics and drug repurposing. Recent advances in OCD genetics support a highly polygenic architecture, implicate specific neuro-biological and immune pathways, and provide new opportunities for clinical translation.

Humans↗

PubMed2025

Exploring depression treatment response by using polygenic risk scoring across diverse populations.

Treatment-resistant depression (TRD), usually defined as limited or no response to at least two antidepressants, occurs in approximately one-third of individuals diagnosed with major depressive disorder (MDD). Studies of individuals of European ancestry highlight a genetic overlap between TRD and MDD. We analyzed two large and diverse biobanks, the UCLA ATLAS Community Health Study (ATLAS) and the All of Us Research Program (AoU), to test for associations between a polygenic score for major depression (MDD-PGS) and TRD. Compared to treatment responders, TRD individuals have higher MDD-PGS across all ancestries. MDD-PGS was significantly associated with response to selective serotonin reuptake inhibitors in individuals of European and Hispanic/Latin American genetic ancestries in both biobanks. In AoU, a decreased MDD-PGS was observed in response to tricyclics or serotonin modulators in individuals of European American ancestry and in response to serotonin and norepinephrine reuptake inhibitors in individuals of African American ancestry. ATLAS found that MDD-PGS showed lower odds of responding to atypical agents than did TRD in MDD-affected individuals belonging to the Hispanic/Latin American group, MDD-PGS was associated with atypical agents. Overall, by leveraging larger sample sizes from two diverse biobanks, we provide new insights into antidepressant response and treatment specificity for MDD in individuals of diverse genetic ancestries.

Adult↗

PubMed2025

Leveraging local ancestry and cross-ancestry genetic architecture to improve genetic prediction of complex traits in admixed populations.

The broader application of polygenic risk score (PRS) is hindered by the limited transferability of PRS developed in Europeans to non-European populations. While many statistical methods have been developed to improve the performance of PRS in non-European populations, most of them focused on discrete genetic ancestry clusters and did not consider admixed individuals. Admixed individuals pose a unique challenge for PRS calculation due to the complexity of local ancestry and cross-ancestry effect sizes. Here, we present a statistical method called SDPR_admix for calculating PRS in admixed individuals. SDPR_admix characterizes the joint distribution of the effect sizes of a genetic variant with two ancestries to be both zero, ancestry enriched, or shared with correlation. SDPR_admix outperformed other methods in simulations and improved the prediction of real traits in European-African admixed individuals in UK Biobank when trained on the Population Architecture using Genomics and Epidemiology (PAGE) dataset (N = 13,000). Deployment of SDPR_admix on All of Us (N = 52,000) further increased the prediction accuracy by approximately 5-fold on average compared with training on PAGE. This enhancement was achieved with manageable computational time and cost, demonstrating the feasibility of training PRS models on large-scale All of Us data. We provided several examples demonstrating that both ancestral-enriched and shared effects, as included in the SDPR_admix prediction model, are helpful for improving polygenic prediction in admixed populations. We also applied SDPR_admix to construct PRS for admixed Americans with mixture of European and Amerindigenous ancestries and showed that SDPR_admix overall outperformed other methods.

Humans↗