55 results found
Davies G, Lam M, Harris SE, et al., 2019, Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (vol 9, 2098, 2018), NATURE COMMUNICATIONS, Vol: 10, ISSN: 2041-1723
Lam M, Trampush JW, Yu J, et al., 2018, Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018), TWIN RESEARCH AND HUMAN GENETICS, Vol: 21, Pages: 394-397, ISSN: 1832-4274
Savage JE, Jansen PR, Stringer S, et al., 2018, Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence, Nature Genetics, Vol: 50, Pages: 912-919, ISSN: 1061-4036
Intelligence is highly heritable1 and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer’s disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Davies G, Lam M, Harris SE, et al., 2018, Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function, Nature Communications, Vol: 9, ISSN: 2041-1723
General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Lam M, Trampush JW, Yu J, et al., 2017, Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets., Cell Reports, Vol: 21, Pages: 2597-2613, ISSN: 2211-1247
Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
Trampush JW, Yang MLZ, Yu J, et al., 2017, GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium (vol 22, pg 336, 2017), Molecular Psychiatry, Vol: 22, Pages: 1651-1652, ISSN: 1359-4184
Trampush J, Zhan Yang ML, Yu J, et al., 2017, GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: A report from the COGENT consortium, Molecular Psychiatry, Vol: 22, Pages: 336-345, ISSN: 1476-5578
The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single nucleotide polymorphisms with minor allele frequency≥1%) to general cognitive function in a sample of 35,298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). Additionally, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genomewide significance level (P<5⨯10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1, and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e. = .01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight, and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.
Need AC, Shashi V, Schoch K, et al., 2016, The importance of dynamic reanalysis In diagnostic whole exome sequencing, Journal of Medical Genetics, Vol: 54, Pages: 155-156, ISSN: 1468-6244
Shashi V, Pena LD, Kim K, et al., 2016, De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype, American Journal of Human Genetics, Vol: 99, Pages: 991-999, ISSN: 1537-6605
The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.
Need AC, Goldstein DB, 2016, Neuropsychiatric Genomics in Precision Medicine: Diagnostics, Gene discovery, and Translation, Dialogues in Clinical Neuroscience, ISSN: 1958-5969
Only a few years after its development, next generation sequencing is rapidly becoming an essential part of clinical care for patients with serious neurological conditions, especially in the diagnosis of early onset and severe presentations. Beyond this diagnostic role, there has been an explosion in definitive gene discovery in a range of neuropsychiatric diseases. This is providing new pointers to underlying disease biology, and beginning to outline a new framework for genetic stratification of neuropsychiatric disease, with clear relevance to both individual treatment optimization and clinical trial design. Here we outline these developments and chart the expected impact on the treatment of neurological, neurodevelopmental and psychiatric disease.
Shashi V, Xie P, Schoch K, et al., 2015, The RBMX gene as a candidate for the Shashi X-linked intellectual disability syndrome, CLINICAL GENETICS, Vol: 88, Pages: 386-390, ISSN: 0009-9163
Zhu X, Petrovski S, Xie P, et al., 2015, Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios, Genetics in Medicine, Vol: 17, Pages: 774-781, ISSN: 1530-0366
Purpose:Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations.Methods:We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients.Results:We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10−8). This enrichment is only partially explained by mutations found in known disease-causing genes.Conclusion:This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.
Enns GM, Shashi V, Bainbridge M, et al., 2014, Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway, GENETICS IN MEDICINE, Vol: 16, Pages: 751-758, ISSN: 1098-3600
Need AC, Goldstein DB, 2014, Schizophrenia Genetics Comes of Age, NEURON, Vol: 83, Pages: 760-763, ISSN: 0896-6273
Nutt DJ, Need AC, 2014, Where now for schizophrenia research?, EUROPEAN NEUROPSYCHOPHARMACOLOGY, Vol: 24, Pages: 1181-1187, ISSN: 0924-977X
Zhu X, Need AC, Petrovski S, et al., 2014, One gene, many neuropsychiatric disorders: lessons from Mendelian diseases, NATURE NEUROSCIENCE, Vol: 17, Pages: 773-781, ISSN: 1097-6256
Tiwari AK, Need AC, Lohoff FW, et al., 2014, Exome sequence analysis of Finnish patients with clozapine-induced agranulocytosis, MOLECULAR PSYCHIATRY, Vol: 19, Pages: 403-405, ISSN: 1359-4184
Shashi V, McConkie-Rosell A, Rosell B, et al., 2014, The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders., Genet Med, Vol: 16, Pages: 176-182
PURPOSE: The purpose of this study was to assess the diagnostic yield of the traditional, comprehensive clinical evaluation and targeted genetic testing, within a general genetics clinic. These data are critically needed to develop clinically and economically grounded diagnostic algorithms that consider presenting phenotype, traditional genetics testing, and the emerging role of next-generation sequencing (whole-exome/genome sequencing). METHODS: We retrospectively analyzed a cohort of 500 unselected consecutive patients who received traditional genetic diagnostic evaluations at a tertiary medical center. We calculated the diagnosis rate, number of visits to diagnosis, genetic tests, and the cost of testing. RESULTS: Thirty-nine patients were determined to not have a genetic disorder; 212 of the remaining 461 (46%) received a genetic diagnosis, and 72% of these were diagnosed on the first visit. The cost per subsequent successful genetic diagnosis was estimated at $25,000. CONCLUSION: Almost half of the patients were diagnosed using the traditional approach, most at the initial visit. For those remaining undiagnosed, next-generation sequencing may be clinically and economically beneficial. Estimating a 50% success rate for next-generation sequencing in undiagnosed genetic disorders, its application after the first clinical visit could result in a higher rate of genetic diagnosis at a considerable cost savings per successful diagnosis.
Smith PJ, Need AC, Cirulli ET, et al., 2013, A comparison of the Cambridge Automated Neuropsychological Test Battery (CANTAB) with "traditional" neuropsychological testing instruments, JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY, Vol: 35, Pages: 319-328, ISSN: 1380-3395
Zhu M, Need AC, Han Y, et al., 2012, Using ERDS to Infer Copy-Number Variants in High-Coverage Genomes, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 408-421, ISSN: 0002-9297
Need AC, McEvoy JP, Gennarelli M, et al., 2012, Exome Sequencing Followed by Large-Scale Genotyping Suggests a Limited Role for Moderately Rare Risk Factors of Strong Effect in Schizophrenia, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 303-312, ISSN: 0002-9297
Heinzen EL, Depondt C, Cavalleri GL, et al., 2012, Exome Sequencing Followed by Large-Scale Genotyping Fails to Identify Single Rare Variants of Large Effect in Idiopathic Generalized Epilepsy, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 293-302, ISSN: 0002-9297
Need AC, Shashi V, Hitomi Y, et al., 2012, Clinical application of exome sequencing in undiagnosed genetic conditions, Journal of Medical Genetics, Vol: 49, Pages: 353-361, ISSN: 1468-6244
BACKGROUND: There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations. METHODS: The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met. RESULTS: This undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features). CONCLUSIONS: This study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.
Pelak K, Need AC, Fellay J, et al., 2011, Copy Number Variation of KIR Genes Influences HIV-1 Control, PLOS BIOLOGY, Vol: 9, ISSN: 1544-9173
Dennis NA, Cabeza R, Need AC, et al., 2011, Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Hippocampal Activation During Episodic Encoding and Retrieval Tasks, HIPPOCAMPUS, Vol: 21, Pages: 980-989, ISSN: 1050-9631
Ge D, Ruzzo EK, Shianna KV, et al., 2011, SVA: software for annotating and visualizing sequenced human genomes, Bioinformatics, Vol: 27, Pages: 1998-2000, ISSN: 1367-4803
SUMMARY: Here we present Sequence Variant Analyzer (SVA), a software tool that assigns a predicted biological function to variants identified in next-generation sequencing studies and provides a browser to visualize the variants in their genomic contexts. SVA also provides for flexible interaction with software implementing variant association tests allowing users to consider both the bioinformatic annotation of identified variants and the strength of their associations with studied traits. We illustrate the annotation features of SVA using two simple examples of sequenced genomes that harbor Mendelian mutations. AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://www.svaproject.org.
Need AC, Goldstein DB, 2010, Whole genome association studies in complex diseases: Where do we stand?, Dialogues in Clinical Neuroscience, Vol: 12, Pages: 34-43, ISSN: 1294-8322
Hundreds of genome-wide association studies have been performed in recent years in order to try to identify common variants that associate with complex disease. These have met with varying success. Some of the strongest effects of common variants have been found in late-onset diseases and in drug response. The major histo-compatibility complex has also shown very strong association with a variety of disorders. Although there have been some notable success stories in neuropsychiatric genetics, on the whole, common variation has explained little of the high heritability of these traits. In contrast, early studies of rare copy number variants have led rapidly to a number of genes and loci that strongly associate with neuropsychiatric disorders. It is likely that the use of whole-genome sequencing to extend the study of rare variation in neuropsychiatry will greatly advance our understanding of neuropsychiatric genetics. © 2010, LLS SAS. All rights reserved.
Pelak K, Shianna KV, Ge D, et al., 2010, The Characterization of Twenty Sequenced Human Genomes, PLOS Genetics, Vol: 6, ISSN: 1553-7390
We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.
Cirulli ET, Kasperaviciute D, Attix DK, et al., 2010, Common genetic variation and performance on standardized cognitive tests, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 18, Pages: 815-819, ISSN: 1018-4813
Dennis NA, Browndyke JN, Stokes J, et al., 2010, Temporal lobe functional activity and connectivity in young adult APOE epsilon 4 carriers, ALZHEIMERS & DEMENTIA, Vol: 6, Pages: 303-311, ISSN: 1552-5260
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