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PubMed2026

Shared genetic architecture between ADHD and intelligence varies across ADHD subtypes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition frequently accompanied by cognitive difficulties. Although previous genetic studies have demonstrated substantial overlap between ADHD and intelligence, most have treated ADHD as a single phenotype. However, whether this shared genetic architecture differs across ADHD subtypes remains unclear. METHODS: We conducted a genome-wide cross-trait analysis integrating large-scale genome-wide association study (GWAS) datasets of overall ADHD, its subtypes-childhood ADHD, persistent ADHD, and late-diagnosed ADHD-and intelligence (total N > 300,000). Genome-wide genetic correlations, polygenic overlap, local genetic correlations, and variant-level associations between ADHD phenotypes and intelligence were evaluated to characterize their shared genetic architecture. Shared variants were identified through cross-trait enrichment analyses and subsequently mapped to genes for functional annotation and gene-set enrichment. Bidirectional associations were evaluated using two-sample Mendelian randomization with sensitivity analyses. Additional GWAS datasets were used to validate the robustness of shared loci by assessing the consistency of effect directions. RESULTS: All ADHD phenotypes showed significant negative genetic correlations with intelligence (rg ranging from -0.3442 to -0.4205). Despite these modest genome-wide correlations, cross-trait analyses revealed substantial genetic overlap, including polygenic overlap, local genetic correlations, and variant-level associations. We identified 184 loci jointly associated with ADHD traits and intelligence, including 64 novel loci, whereas no shared loci were detected for persistent ADHD under the current analysis. Functional annotation revealed biologically distinct enrichment patterns across subtypes: childhood ADHD loci were linked to early neurodevelopmental processes, while late-diagnosed ADHD loci were enriched in synapse-related and neuronal signaling pathways. Mendelian randomization analyses suggested bidirectional associations, with stronger evidence supporting a directional association from intelligence to ADHD risk. Furthermore, these shared loci showed largely consistent effect directions across additional GWAS datasets, providing support for the robustness of the findings. CONCLUSIONS: The shared genetic architecture between ADHD and intelligence varies across ADHD subtypes, highlighting distinct biological pathways underlying cognitive heterogeneity in ADHD. These findings suggest that the relationship between ADHD liability and general cognitive ability is not uniform across ADHD subtypes and may inform future research on risk stratification and early identification in child and adolescent psychiatry.

Humans↗

PubMed1989

Benign partial epilepsy and related conditions: multifactorial pathogenesis with hereditary impairment of brain maturation.

The main clinical and bioelectrical features of the benign partial epilepsies and related conditions are described. Based on highly selected groups, the definition of these suggested syndromes disregards the considerable overlap between borderline and intermediate cases. To understand the great phenotypic variability of these epilepsies, the complexity of causal especially genetic factors must be considered. Different genetic traits, expressed in certain EEG patterns, determine the level of cerebral excitability. These hereditary variables are widespread in the general population. Most are polygenic, focal sharp waves possibly autosomal dominant. In individuals, the coincidence of different traits with little or no clinical significance, results in additive effects lowering the seizure threshold and raising the risk of clinical manifestation. The complexity of causal factors, which, potentially include organic brain lesions, account for the wide spectrum of epileptic and non-epileptic conditions ranging from mild selective performance deficits to complex psychomental retardation, and from simple rolandic epilepsy to severe epilepsies with minor seizures or bioelectrical status. These conditions are not "syndromes" in the stricter sense, but sets of variably weighted symptoms of a complex pathogenetic background. A genetic disposition to focal pathogenetic background. A genetic disposition to focal anomalies of brain function is of decisive importance. The biological background is as of yet unknown. The marked age-dependency of symptoms and almost regular disappearance of seizures and EEG abnormalities at puberty justify the assumption of an hereditary impairment of brain maturation. The hypothesis of autosomal dominant inheritance awaits appraisal by studies of larger populations and quantitative genetic approaches.

Adolescent↗

PubMed1996

Genetic analysis of the cause of gastroschisis in the HLG mouse strain.

An inbred mouse strain HLG shows a high incidence of gastroschisis after X-ray exposure to the zygotes. About 11% of the fetuses display this malformation after irradiation with 1 Gy. The C57BL-strain does not show the increased frequency of gastroschisis after radiation-exposure to the zygotes. The genetic background of this malformation was investigated in a backcross of HLG x C57BL females to HLG males. The pregnant HLG x C57BL females were irradiated in a stage in which the (HLG x C57BL) x HLG [BC1] embryos were in the 1-cell stage. The frequency of gastroschisis in the BC1 generation was compared with a genetic model of a single recessive mutation with 11% penetrance. This frequency does not fit a single-locus inheritance. The number of loci involved was estimated to be about two or three. HLG mouse strain may be a valuable animal model in the study of polygenic traits.

Abdominal Muscles↗

PubMed2001

[Colon cancer and nutritional genetics: modifier genes].

About 5% of colon cancer cases correspond to classic hereditary monogenic mendelian transmission involving at least 8 major genes of predisposition to this tumor. Genes with more moderate effects, in association with other genes can contribute to the occurrence of sporadic polygenic forms. These genes confer susceptibility to environmental factors and can play the role of aggravating or protective modifier genes in the different hereditary forms. Foods can interact with these genes and modulate their expression. Moreover sequence variations (polymorphisms) in these genes may also be responsible for slower or more rapid metabolism of nutrients leading to toxic or carcinogenic compounds. If some foods, or "pharmafoods" can have beneficial effects in some individuals with a particular subtype of the disease, others can be inefficient or even detrimental in patients with the same disease but with a different genetic origin or if the genetic background is different. Moreover tumorigenic processes are diverse. Tumor progression depends on genetic and environmental factors different from tumor initiation and on the site of the tumor along the colon tract. Interactions with the gut flora, the lymphoid system and specific features of growth of the colon mucosa are also important parameters. Today with a formidable genetic knowledge arising from the genome project, new epidemiological data integrating the genetic data for multiple markers and a better knowledge of the tumorigenic processes involved, a new discipline is emerging. "Nutrigenetics" which is the study of hereditary basis of individual variations in response to foods opens for the oncoming decade the era of a personalised predictive medecine based on a nutrition adapted to the genetic make up of each of us.

Cocarcinogenesis↗

PubMed2005

Genetic polymorphisms and sepsis.

Sepsis is a polygenic and complex syndrome that is initiated by infection and is characterized by a systemic inflammatory response. Genetic polymorphisms in the immune response to infection have been shown to be associated with clinical outcomes. Functional and association studies involving genetic polymorphisms in essential genes, including Toll-like receptors, cytokines, and coagulation factors, have provided important insights into the mechanisms involved in the pathogenesis of sepsis-induced organ dysfunction. The advancement of high-throughput single nucleotide polymorphism (SNP) genotyping will provide valuable information on the interaction of multiple allelic variants and clinical outcome. More precise categorization of patients based on genetic background is likely to lead to individualized targeted treatment. Future therapeutic trials as well as actual treatment regimens for patients with sepsis are likely to be designed to target specific genotypes and associated cellular responses, maximizing clinical response and patient safety.

Animals↗

PubMed2026

Arrhythmia and cardiomyopathy risk in Taiwan with complementary biobank evidence on thyroid genetic susceptibility: an integrative population-based framework.

BACKGROUND: Arrhythmia-induced cardiomyopathy (AiCM) is a potentially reversible cause of ventricular dysfunction; however, only a subset of patients with arrhythmia develop cardiomyopathy. Emerging evidence suggests that endocrine factors, particularly thyroid dysfunction with genetic susceptibility, may contribute to inter-individual variability in arrhythmia-related myocardial outcomes. METHODS: We performed a dual-cohort population-based study using the National Health Insurance Research Database (NHIRD, 2000-2015) and the Taiwan Biobank (TWB). In NHIRD, we examined the association between newly diagnosed arrhythmia and incident cardiomyopathy using Cox proportional hazards models. In TWB, genome-wide data, thyroid-stimulating hormone (TSH), polygenic risk scores (PRSs), lifestyle factors, and metabolic comorbidities were analyzed using multivariable regression and interaction models to assess determinants of thyroid dysfunction. RESULTS: In the NHIRD cohort, arrhythmia was associated with a significantly increased risk of incident cardiomyopathy (adjusted hazard ratio (aHR): 2.49, 95% CI: 1.94-2.96), with atrial fibrillation showing the strongest association among arrhythmia subtypes. In the TWB cohort, a higher thyroid polygenic risk score was strongly associated with thyroid dysfunction (adjusted odds ratio (aOR): 6.64, 95% CI: 5.86-7.52). The association between genetic susceptibility and thyroid dysfunction was further modified by metabolic and lifestyle factors, including diabetes, hyperlipidemia, and dietary patterns. Genome-wide analysis identified multiple loci associated with thyroid-stimulating hormone regulation, consistent with a polygenic architecture of thyroid endocrine traits. CONCLUSION: Arrhythmia was associated with an increased risk of cardiomyopathy in a nationwide cohort, while thyroid genetic susceptibility was strongly associated with thyroid dysfunction in a biobank cohort and modified by metabolic and lifestyle factors. These findings provide complementary population-level evidence of parallel cardiovascular and endocrine-genetic associations. Because the two cohorts were not individually linked, causal inference cannot be established. The results support a systems-level framework of endocrine-cardiac interaction and suggest that integrated clinical and genetic risk assessment may help identify individuals who warrant closer monitoring.

arrhythmia↗

PubMed1999

Path analysis of P300 amplitude of individuals from families at high and low risk for developing alcoholism.

BACKGROUND: A substantial amount of evidence exists suggesting that P300 amplitude in childhood is a risk marker for later development of alcohol dependence. There is evidence that P300 amplitude is heritable. The goal of the present study was to determine if patterns of transmission differed in families who were either at high or low risk for developing alcohol dependence. METHODS: Auditory P300 was recorded from 536 individuals spanning three generations. The path analytic TAU model was used to investigate the familial transmission of P300 amplitude in the two independent samples of families. RESULTS: Transmission of P300 in high-risk families most likely followed a polygenic model of inheritance with significant parent-to-offspring transmission. Parent-to-offspring transmission was significantly greater in high-risk than low-risk families. Total phenotypic variance due to transmissible factors was greater in low-risk families than in high-risk families, however. A somewhat unexpected finding was the substantial correlation between mates for P300 amplitude in both high- and low-risk families. CONCLUSIONS: P300 is transmissible in families. Differences exist in the pattern of transmission for P300 in families at high and low risk for alcoholism.

Adolescent↗

PubMed2004

[Genetic background of epilepsies].

In this article we review epilepsies with monogenic inheritance. Most of these diseases are caused by abnormal function of ligand- and voltage gated ion channels caused by a genetic defect, therefore belonging to the channelopathies. From the inherited epilepsies the genetics of the autosomal dominant partial epilepsies is clarified the best. Mutations of the nicotinic acetylcholine receptor subunits are found in familial nocturnal frontal lobe epilepsy, while defects in the voltage gated potassium channels (KCNQ2 and KCNQ3) have been identified in benign familial neonatal convulsions. Familial temporolateral epilepsy was associated with mutations of a tumor suppressor gene. From the generalized epilepsies, the syndrome of generalized epilepsy with febrile seizures plus (GEFS+) can be caused by mutations of the sodium channel subunits and of the GABAA receptor subunits. These important results would probably lead to new findings in the genetics of the more common forms of idiopathic generalized epilepsies, which have presumed polygenic origin. Although without definite conclusions, sodium channel and GABA receptor dysfunction is presumed. The accumulated knowledge about channelopathies enables insight to the cellular mechanism of epileptogenesis as well.

Chromosomes, Human, X↗

PubMed2004

[Genetics and immunopathogenics aspects of the celiac disease: a recent vision].

BACKGROUND: Celiac disease, or gluten-sensitive enteropathy, is a strongly inherited condition. Although the genetic association of CD with the DQ2 and DQ8 HLA haplotypes has been known for long, others HLA and non-HLA genes are also important in the development of the disease. Celiac disease results of the combined effect of different normally functioning genes' products. The tissue damage in celiac disease is immunologically mediated and several effector mechanisms are responsible for the disease expression. The interplay between genetic, immunological and environmental factors explains the large spectrum of clinical, histological and serological alterations observed in the different stages of the disease development, pointing out to the polygenic nature of celiac disease. CONCLUSION: The recent advances in the understanding of the immunopathogenesis, genetics and diagnoses of celiac disease have allowed the revision of strict concepts and previous criteria and their adequation to the new evidences, aiming a better diagnostic and orientation to celiac patients and relatives.

Celiac Disease↗

PubMed2026

Metabolomic ageing across mental and behavioural disorders.

BACKGROUND: Individuals with mental disorders face excess morbidity and premature mortality. Accelerated ageing has been proposed as a contributing mechanism but population-scale evidence across diverse diagnoses is limited. OBJECTIVE: To examine whether metabolomic ageing differs across mental disorders and whether associations vary by sex, age group and genetic liability. METHODS: Using plasma metabolomic profiles from UK Biobank participants, we applied a metabolomic ageing clock (MileAge) to estimate disorder-specific differences between metabolite-predicted and chronological age. Mental disorders were ascertained from health records and self-reported physician diagnoses. We analysed nine diagnostic groups and 45 individual disorders and assessed sex and age group differences and associations with polygenic scores. FINDINGS: Among 225 212 participants (54% female; mean age 56.97), 38 524 had a diagnosis preceding baseline. Substance use, psychotic, affective and neurotic disorders were associated with a metabolite-predicted age older than chronological age, largest for psychosis (β=0.556, 95% CI 0.250 to 0.861, p<0.001). Obsessive-compulsive and eating disorders were associated with a metabolite-predicted age younger than chronological age. Several associations were stronger in males and in individuals aged <65 years. Higher genetic liability to depression, autism and attention-deficit/hyperactivity disorder predicted an older metabolomic age (β range=0.020 to 0.047), whereas polygenic scores for psychosis and tobacco use disorder predicted a younger metabolomic age (β range=-0.023 to -0.040). For obsessive-compulsive disorder and anorexia nervosa, clinical and genetic associations indicated younger metabolomic ageing. CONCLUSIONS: Metabolomic ageing in mental disorders is heterogeneous. While many disorders are associated with an older biological age, some are linked to a younger biological age. Divergence between genetic liability and clinical phenotypes suggests that non-genetic factors shape biological ageing differences. CLINICAL IMPLICATIONS: Biological age should not be assumed to uniformly exceed chronological age across mental disorders. Sex and age-specific approaches could improve understanding of biological ageing processes in psychiatry.

Humans↗

PubMed2025

Blood Pressure Genetics in Han Taiwanese With Cross-Trait Analysis in East Asians: Insights Into Comorbidities, All-Cause Mortality, and Cardiovascular Mortality.

BACKGROUND: Hypertension is a major health burden in East Asia. However, the genetic architecture and clinical implications of blood pressure (BP) traits remain underexplored beyond European-focused studies. This large-scale study aimed to investigate hypertension, systolic BP, and diastolic BP, to uncover genetic links to comorbidities and mortality in Han Taiwanese individuals. METHODS: This large-scale study used China Medical University Hospital biobank data and conducted genome-wide association studies on 25 523 hypertension cases and 47 522 controls, plus 66 236 individuals for systolic BP and 66 152 for diastolic BP. Cross-trait genetic correlations were assessed across 5 East Asian biobanks. Mendelian randomization and polygenic risk scores were applied to assess causality and predict clinical outcomes. RESULTS: We identified 8 loci and 36 genes for hypertension, 7 loci and 17 genes for systolic BP, and 9 loci and 26 genes for diastolic BP. ATP2B1 and FGF5 were common to all BP traits, implicating calcium signaling and vascular remodeling pathways. Cross-trait analyses showed shared genetic liability between BP traits and cardiovascular and metabolic comorbidities. Phenome-wide association studies confirmed strong associations with circulatory diseases. Mendelian randomization analyses demonstrated that elevated BP causally increases the risk of unstable angina pectoris. Polygenic risk scores predicted significantly higher risks and earlier onset of unstable angina pectoris, all-cause mortality, and cardiovascular mortality among individuals in the top polygenic risk score quintiles. CONCLUSIONS: Our findings highlight the genetic basis of BP and comorbidities in East Asians, suggesting that BP genetic risk may inform future approaches to early risk assessment and prevention.

Aged↗

PubMed2000

Genetics of systemic autoimmunity in mouse models of lupus.

Systemic lupus erythematosus (SLE) is inherited as a complex polygenic trait, involving genetic, environmental and stochastic factors. Although definition of these etiologic processes has been elusive, solid progress has been made toward elucidating the genetic basis for susceptibility. Herein, we summarize our genome wide mapping effort that has defined loci for component phenotypes for lupus-prone NZB, NZW, MRL-Fas(lpr) and BXSB strains. With this framework in place, identification of the specific genetic alterations and mechanisms is now proceeding through the generation of interval congenic lines, precise mapping and screening of candidate genes. In addition to this approach, transgenic and gene knockout studies have begun to identify genes that can induce or modify autoimmunity in nonautoimmune and lupus-prone background mice, including studies by us and others on Th1 and Th2 cytokine genes in lupus. It is apparent that a diversity of genes and mechanisms can independently or in combination promote systemic autoimmunity in mice. This complexity, which is also observed in human lupus, emphasizes the importance of using experimental and less complex mouse models to define these processes, a tactic that has already yielded new insights. With current technologies and the anticipated definition of mammalian genomes, identification of genes predisposing to lupus and elucidation of processes critical for disease pathogenesis appear within grasp.

Animals↗

PubMed2026

Context-specific genetic effects inform endotypes and treatment in asthma.

BACKGROUND: Asthma has heterogeneous risk factors, subtypes, and treatments. It is often unclear how to stratify this heterogeneity in scientific studies and clinical care. Genetics could explain root causes of this clinical heterogeneity, called endotypes, but prior studies have used models that are not designed for complex diseases like asthma. OBJECTIVE: We aimed to find genetic effects that partly explain different asthma endotypes. METHODS: We used recent powerful and robust statistical models of context-specific genetic effects in complex traits. We identified genetic subtypes by clustering clinical asthma features in a case-control cohort, GALA II. We replicated the genetic endotypes in the UK Biobank with gene-context interaction tests. RESULTS: Asthma-associated single nucleotide polymorphisms, polygenic scores, and genome-wide heritability revealed subtype-specific genetic endotypes correlated with type 2 inflammation, allergy, and neuroticism. We validated the type 2 associations with molecular data including nasal RNA sequencing. In the UK Biobank, we replicated these endotypes and found they interact with several polygenic scores and drug-relevant genes. CONCLUSION: Our results show how context-specific genetic effects can unravel biomedically meaningful endotypes of complex disease and suggest novel precision treatment strategies.

Humans↗

PubMed2025

Genetic Differences in Reactivity to the Environment Impact Psychotic-Like and Affective Reactivity in Daily Life.

BACKGROUND AND HYPOTHESIS: Consistent with diathesis-stress models, psychosis research has focused on genetic moderation of adverse environmental exposures. In contrast, the Differential Susceptibility (DS) model suggests that the same genetic variants that increase risk-inducing effects of adverse experiences also enhance beneficial effects from positive experiences. This study examined whether individuals with high genetic susceptibility to the environment showed differential psychotic-like and affective reactivity in response to positive and negative events in daily life. STUDY DESIGN: Experience sampling methodology assessed context (positive and stressful) and momentary levels of paranoia, psychotic-like experiences (PLE), and positive (PA) and negative affect (NA) in 217 non-clinical adults oversampled for schizotypy. Linear mixed models examined whether Polygenic Risk Scores of Environmental Sensitivity (PRS-ES) moderated the impact of current context on subsequent experiences. STUDY RESULTS: PRS-ES moderated positive, but not stressful, context on subsequent levels of momentary paranoia, NA, and PA, but not PLE. Genetic and environmental (G × E) interactions indicated diathesis-stress at lower thresholds of PRS-ES, but a DS model at the highest threshold of the PRS-ES. Participants with elevated PRS-ES showed increased paranoia and NA and decreased PA in subsequent assessments when reporting low levels of positive situations, but also decreased paranoia and NA and increased PA when rating contexts as positive. CONCLUSIONS: Findings support the influence of genetic sensitivity to the environment on psychotic-like and affective reactivity in daily life, particularly in response to positive contexts. This highlights the transdiagnostic protective role of positive experiences and informs ecological momentary interventions.

Humans↗

PubMed2004

Genetics of hybrid incompatibility between Lycopersicon esculentum and L. hirsutum.

We examined the genetics of hybrid incompatibility between two closely related diploid hermaphroditic plant species. Using a set of near-isogenic lines (NILs) representing 85% of the genome of the wild species Lycopersicon hirsutum (Solanum habrochaites) in the genetic background of the cultivated tomato L. esculentum (S. lycopersicum), we found that hybrid pollen and seed infertility are each based on 5-11 QTL that individually reduce hybrid fitness by 36-90%. Seed infertility QTL act additively or recessively, consistent with findings in other systems where incompatibility loci have largely been recessive. Genetic lengths of introgressed chromosomal segments explain little of the variation for hybrid incompatibility among NILs, arguing against an infinitesimal model of hybrid incompatibility and reinforcing our inference of a limited number of discrete incompatibility factors between these species. In addition, male (pollen) and other (seed) incompatibility factors are roughly comparable in number. The latter two findings contrast strongly with data from Drosophila where hybrid incompatibility can be highly polygenic and complex, and male sterility evolves substantially faster than female sterility or hybrid inviability. The observed differences between Lycopersicon and Drosophila might be due to differences in sex determination system, reproductive and mating biology, and/or the prevalence of sexual interactions such as sexual selection.

Chromosome Mapping↗

PubMedDate not supplied

The genes of systemic autoimmunity.

Autoimmune diseases include a wide spectrum of disorders, which have been divided into systemic and organ-specific disorders. Lupus, the prototypic systemic autoimmune disease, is characterized by female predominance, multiorgan pathology, and autoantibodies, primarily directed against nuclear antigens. The disease is heterogeneous, with variable organ involvement, serology, and clinical course. Susceptibility to lupus is inherited as a polygenic trait with added contributions from environmental and stochastic variance. Concerted efforts have recently been made by several laboratories to define the genetic basis of this disease in predisposed mice and humans. The identification of the Fas/FasL defects in lpr and gld lupus mice was the first example of spontaneous mutations of apoptosis-promoting genes being associated with systemic autoimmunity. This research was instrumental in clarifying the roles of these genes in tolerance and immunoregulation, and in extrapolating these results to other autoimmune diseases, as well as cancer and transplantation. To these findings have been added those from transgenic and gene knockout mouse studies that have helped to define the systemic autoimmunity-inducing or -modifying effects of specific genes in normal background and lupus-congenic mice. In addition, the findings from genome-wide searches have begun to identify predisposing loci (and ultimately genes) for the spontaneous lupus-like diseases in various mouse strains and in humans. The emerging picture is that multiple genetic contributions can independently lead to systemic autoimmunity in mice, which reinforces the view that human lupus may be similarly composed of diverse genotypes. This complexity underscores the importance of defining the predisposing alleles and mechanisms of action, an undertaking that is certainly feasible given current technologies and future advances in the definition of mammalian genomes.

Animals↗

PubMed1991

Dominant low responsiveness in the IgG response of mice to the complex protein antigen type 1 fimbriae from Actinomyces viscosus T14V.

Type 1 fimbriae from Actinomyces viscosus T14V, composed of a complex protein of Mr 65,000, mediate the adherence of A. viscosus T14V to the host, whereas type 1 fimbriae-specific antibodies inhibit adherence. Genetic control of the serum IgG response to type 1 fimbriae was evaluated in a series of inbred, hybrid, recombinant inbred, and back-cross mice. Mice were given i.p. injections of 10(8) A. viscosus T14V cells in saline on days 0 and 14, and IgG anti-type 1 fimbriae in sera obtained on day 26 were measured by ELISA. Segregation analysis of the responses of (BALB/cJ x A/J)F1 x A/J backcross mice suggested polygenic control. Linkage analysis in (BALB/cJ x A/J)F1 x A/J backcross and SWXL recombinant inbred mice suggested control by genes linked with H-2 and with Ly-17 and Akp-1. In several F1 hybrid strains derived from H-2-disparate high and low responder parental strains, low responsiveness was dominant. The F1 derived from the H-2-identical high and low responder strains CBA/J and C3H/HeJ was a low responder, suggesting that dominant low responsiveness was mediated by non-H-2-linked genes. A three-gene model is proposed for regulation of the type 1 fimbriae response, including an MHC-linked gene, a gene linked with Ly-17 and Akp-1 on the telomeric portion of chromosome 1, and a background gene whose linkage is unknown.

Actinomyces↗

PubMed2026

Shared genetic basis and structure of syndromic and normal facial variation.

The question of how gene mutations of large effect and common variants of small effect relate to phenotypic variation dates from the origins of genetics. Mendelian diseases result from rare germline variants with major effects, while complex traits are associated with multiple, mostly common variants of small effect. High-dimensional phenotypes, such as facial shape, can shed new light on this age-old dichotomy, as their variation can be characterized in terms of directions in multivariate morphospace. Within such spaces, do Mendelian disease mutations move phenotypes along the same directions as common variants, or do they forge new directions that diverge from the common structure of background variation? Here, we analyze facial shape variation for 66 syndromes, quantify multivariate axes of facial shape variation for each syndrome, and test whether common genetic variants in cohorts of non-syndromic subjects are associated with phenotypic position along these same axes. We find that syndromic facial shape generally follows the background variance-covariance structure of facial shape in the general population. Furthermore, syndromic probands' unaffected relatives have subtle facial morphology resembling the syndromes of their affected relatives. These results suggest that Mendelian disease variants act on facial shape in ways similar to common variants. Syndromic probands with higher "severity" likely occur on genetic backgrounds with higher cumulative severity of common variants for each syndromic axis. These findings position Mendelian diseases at extremes along phenotypic continua that exist in the background population rather than as qualitatively different phenotypes distinct from the overall structure of normal human phenotypic variation.

Humans↗