Effects-sizes of deletions and duplications on autism risk across the genome

ABSTRACTObjectiveDeleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, only 13 genomic loci have been formally associated with autism because the majority of CNVs are too rare to perform individual association studies. To investigate the implication of undocumented CNVs in neurodevelopmental disorders, we recently developed a new framework to estimate their effect-size on intelligence quotient (IQ) and sought to extend this approach to autism susceptibility and multiple cognitive domains.MethodsWe identified CNVs in two autism samples (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models integrating scores of genes encompassed in CNVs were used to explain their effect on autism susceptibility and multiple cognitive domains.ResultsAmong 9 scores of genes, the “probability-of-being loss-of-function intolerant” (pLI) best explains the effect of CNVs on IQ and autism risk. Deletions decrease IQ by a mean of 2.6 points per point of pLI. The effect of duplications on IQ is three-fold smaller. The odd ratios for autism increases when deleting or duplicating any point of pLI. This increased autism risk is similar in subgroups of individuals below or above median IQ. Once CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behaviour, and phonological memory, whereas both equally affect motor skills.ConclusionsAutism risk conferred by duplications is less influenced by IQ compared to deletions. CNVs increase autism risk similarly in individuals with high and low IQ. Our model, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk. These models will help interpreting CNVs identified in the clinic.

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Genetic architecture of schizophrenia: a review of major advancements

Psychological Medicine ◽

10.1017/s0033291720005334 ◽

2021 ◽

pp. 1-10

Author(s):

Sophie E. Legge ◽

Marcos L. Santoro ◽

Sathish Periyasamy ◽

Adeniran Okewole ◽

Arsalan Arsalan ◽

...

Keyword(s):

Genetic Architecture ◽

Association Studies ◽

Copy Number Variants ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Genetic Loci ◽

Significant Enrichment ◽

High Heritability ◽

Coding Variants

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

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GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

Nature Communications ◽

10.1038/s41467-021-24563-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lucas D. Ward ◽

Ho-Chou Tu ◽

Chelsea B. Quenneville ◽

Shira Tsour ◽

Alexander O. Flynn-Carroll ◽

...

Keyword(s):

Bile Duct ◽

Extrahepatic Bile Duct ◽

Association Studies ◽

Missense Variant ◽

Deficiency Anemia ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Extrahepatic Bile Duct Cancer ◽

Hepatocellular Damage ◽

Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

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Cis-Segregation of c.1171C>T Stop Codon (p.R391*) in SERPINC1 Gene and c.1691G>A Transition (p.R506Q) in F5 Gene and Selected GWAS Multilocus Approach in Inherited Thrombophilia

Genes ◽

10.3390/genes12060934 ◽

2021 ◽

Vol 12 (6) ◽

pp. 934

Author(s):

Donato Gemmati ◽

Giovanna Longo ◽

Eugenia Franchini ◽

Juliana Araujo Silva ◽

Ines Gallo ◽

...

Keyword(s):

At Risk ◽

Stop Codon ◽

Association Studies ◽

Premature Stop Codon ◽

Large Family ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Gene Markers ◽

Inherited Thrombophilia ◽

Fv Leiden

Inherited thrombophilia (e.g., venous thromboembolism, VTE) is due to rare loss-of-function mutations in anticoagulant factors genes (i.e., SERPINC1, PROC, PROS1), common gain-of-function mutations in procoagulant factors genes (i.e., F5, F2), and acquired risk conditions. Genome Wide Association Studies (GWAS) recently recognized several genes associated with VTE though gene defects may unpredictably remain asymptomatic, so calculating the individual genetic predisposition is a challenging task. We investigated a large family with severe, recurrent, early-onset VTE in which two sisters experienced VTE during pregnancies characterized by a perinatal in-utero thrombosis in the newborn and a life-saving pregnancy-interruption because of massive VTE, respectively. A nonsense mutation (CGA > TGA) generating a premature stop-codon (c.1171C>T; p.R391*) in the exon 6 of SERPINC1 gene (1q25.1) causing Antithrombin (AT) deficiency and the common missense mutation (c.1691G>A; p.R506Q) in the exon 10 of F5 gene (1q24.2) (i.e., FV Leiden; rs6025) were coinherited in all the symptomatic members investigated suspecting a cis-segregation further confirmed by STR-linkage-analyses [i.e., SERPINC1 IVS5 (ATT)5–18, F5 IVS2 (AT)6–33 and F5 IVS11 (GT)12–16] and SERPINC1 intragenic variants (i.e., rs5878 and rs677). A multilocus investigation of blood-coagulation balance genes detected the coexistence of FV Leiden (rs6025) in trans with FV HR2-haplotype (p.H1299R; rs1800595) in the aborted fetus, and F11 rs2289252, F12 rs1801020, F13A1 rs5985, and KNG1 rs710446 in the newborn and other members. Common selected gene variants may strongly synergize with less common mutations tuning potential life-threatening conditions when combined with rare severest mutations. Merging classic and newly GWAS-identified gene markers in at risk families is mandatory for VTE risk estimation in the clinical practice, avoiding partial risk score evaluation in unrecognized at risk patients.

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Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

Cancers ◽

10.3390/cancers13112704 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2704

Author(s):

Sally Yepes ◽

Nirav N. Shah ◽

Jiwei Bai ◽

Hela Koka ◽

Chuzhong Li ◽

...

Keyword(s):

Internal Control ◽

Susceptibility Gene ◽

Copy Number Variants ◽

Bone Cancer ◽

Chinese Patients ◽

European Ancestry ◽

Unknown Etiology ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Pathogenic Variants

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

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Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.679568 ◽

2021 ◽

Vol 15 ◽

Author(s):

Bin Li ◽

Guihu Zhao ◽

Qiao Zhou ◽

Yali Xie ◽

Zheng Wang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Association Studies ◽

Age At Onset ◽

Genetic Data ◽

Genome Wide Association Studies ◽

Onset Age ◽

Loss Of Function

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.

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Characterizing a common CERS2 polymorphism in a mouse model of metabolic disease and in subjects from the Utah CAD Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab155 ◽

2021 ◽

Author(s):

Rebekah J Nicholson ◽

Annelise M Poss ◽

J Alan Maschek ◽

James E Cox ◽

Paul N Hopkins ◽

...

Keyword(s):

Metabolic Disease ◽

Coronary Artery Disease ◽

Enzyme Activity ◽

Coronary Artery ◽

Association Studies ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Serum Samples ◽

Artery Disease ◽

Disease Study

Abstract Context Genome-wide association studies have identified associations between a common single nucleotide polymorphism (SNP, rs267738) in CERS2 – a gene that encodes a (dihydro)ceramide synthase involved in the biosynthesis of very-long chain sphingolipids (e.g. C20-C26) – and indices of metabolic dysfunction (e.g. impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved. Objective The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes. Design We performed in-depth lipidomic and metabolic characterization of a novel CRISPR knock-in mouse modeling the rs267738 variant. In parallel, we conducted mass spectrometry-based, targeted lipidomics on 567 serum samples collected through the Utah Coronary Artery Disease study, which included 185 patients harboring one (n = 163) or both (n = 22) rs267738 alleles. Results In-silico analysis of the amino acid substitution within CERS2 caused by the rs267738 mutation suggested that rs267738 is deleterious for enzyme function. Homozygous knock-in mice had reduced liver CERS2 activity and enhanced diet-induced glucose intolerance and hepatic steatosis. However, human serum sphingolipids and a ceramide-based CERT1 risk score of cardiovascular disease were not significantly affected by rs267738 allele count. Conclusions The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study.

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Dominant maternal-effect mutations causing embryonic lethality in Caenorhabditis elegans.

Genetics ◽

10.1093/genetics/125.2.351 ◽

1990 ◽

Vol 125 (2) ◽

pp. 351-369 ◽

Cited By ~ 3

Author(s):

P E Mains ◽

I A Sulston ◽

W B Wood

Keyword(s):

Caenorhabditis Elegans ◽

Maternal Effect ◽

Gene Dosage ◽

Recessive Mutation ◽

Dominant Male ◽

Temperature Sensitive ◽

Male Mating ◽

Loss Of Function ◽

Dominant Mutant ◽

Embryonic Viability

Abstract We undertook screens for dominant, temperature-sensitive, maternal-effect embryonic-lethal mutations of Caenorhabditis elegans as a way to identify certain classes of genes with early embryonic functions, in particular those that are members of multigene families and those that are required in two copies for normal development. The screens have identified eight mutations, representing six loci. Mutations at three of the loci result in only maternal effects on embryonic viability. Mutations at the remaining three loci cause additional nonmaternal (zygotic) effects, including recessive lethality or sterility and dominant male mating defects. Mutations at five of the loci cause visible pregastrulation defects. Three mutations appear to be allelic with a recessive mutation of let-354. Gene dosage experiments indicate that one mutation may be a loss-of-function allele at a haploin sufficient locus. The other mutations appear to result in gain-of-function "poison" gene products. Most of these become less deleterious as the relative dosage of the corresponding wild-type allele is increased; we show that relative self-progeny viabilities for the relevant hermaphrodite genotypes are generally M/+/+ greater than M/+ greater than M/M/+ greater than M/Df greater than M/M, where M represents the dominant mutant allele.

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HAND1 loss-of-function within the embryonic myocardium reveals survivable congenital cardiac defects and adult heart failure

Cardiovascular Research ◽

10.1093/cvr/cvz182 ◽

2019 ◽

Vol 116 (3) ◽

pp. 605-618 ◽

Cited By ~ 1

Author(s):

Beth A Firulli ◽

Rajani M George ◽

Jade Harkin ◽

Kevin P Toolan ◽

Hongyu Gao ◽

...

Keyword(s):

Heart Failure ◽

Gene Dosage ◽

Diastolic Heart Failure ◽

Heart Defects ◽

Conduction System ◽

Cardiac Conduction ◽

Bhlh Transcription Factor ◽

Loss Of Function ◽

Regulatory Pathways ◽

Morphological Alterations

Abstract Aims To examine the role of the basic Helix-loop-Helix (bHLH) transcription factor HAND1 in embryonic and adult myocardium. Methods and results Hand1 is expressed within the cardiomyocytes of the left ventricle (LV) and myocardial cuff between embryonic days (E) 9.5–13.5. Hand gene dosage plays an important role in ventricular morphology and the contribution of Hand1 to congenital heart defects requires further interrogation. Conditional ablation of Hand1 was carried out using either Nkx2.5 knockin Cre (Nkx2.5Cre) or α-myosin heavy chain Cre (αMhc-Cre) driver. Interrogation of transcriptome data via ingenuity pathway analysis reveals several gene regulatory pathways disrupted including translation and cardiac hypertrophy-related pathways. Embryo and adult hearts were subjected to histological, functional, and molecular analyses. Myocardial deletion of Hand1 results in morphological defects that include cardiac conduction system defects, survivable interventricular septal defects, and abnormal LV papillary muscles (PMs). Resulting Hand1 conditional mutants are born at Mendelian frequencies; but the morphological alterations acquired during cardiac development result in, the mice developing diastolic heart failure. Conclusion Collectively, these data reveal that HAND1 contributes to the morphogenic patterning and maturation of cardiomyocytes during embryogenesis and although survivable, indicates a role for Hand1 within the developing conduction system and PM development.

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Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

Journal of Clinical Medicine ◽

10.3390/jcm9041096 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1096

Author(s):

Jessica Gambardella ◽

Angela Lombardi ◽

Marco Bruno Morelli ◽

John Ferrara ◽

Gaetano Santulli

Keyword(s):

Human Disease ◽

Calcium Release ◽

Current Knowledge ◽

Association Studies ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Genome Wide ◽

Inositol 1,4,5 Trisphosphate ◽

Human Disorders

Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.

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Association of CNVs with methylation variation

npj Genomic Medicine ◽

10.1038/s41525-020-00145-w ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Xinghua Shi ◽

Saranya Radhakrishnan ◽

Jia Wen ◽

Jin Yun Chen ◽

Junjie Chen ◽

...

Keyword(s):

Association Studies ◽

Copy Number Variants ◽

Cpg Methylation ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Cellular Phenotype ◽

Genome Wide ◽

A Genome ◽

Physical Interactions ◽

Trait Locus

Abstract Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with gene expression. CNV-mQTLs were enriched for regulatory regions, transcription factor-binding sites (TFBSs), and were involved in long-range physical interactions with associated CpGs. Some CNV-mQTLs were associated with methylation of imprinted genes. Several CNV-mQTLs and/or associated genes were among those previously reported by genome-wide association studies (GWASs). We demonstrate that germline CNVs in the genome are associated with CpG methylation. Our findings suggest that structural variation together with methylation may affect cellular phenotype.

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