Dr. Khera is a physician-scientist with expertise in epidemiology, clinical medicine, and human genetics. Among his scientific contributions, he pioneered a new approach to quantify genetic risk for common diseases, […]
Research Domain: Identification of Underlying Genes
Heidi L. Rehm
Heidi Rehm is the Chief Genomics Officer in the Department of Medicine and at the Center for Genomic Medicine, the Medical Director of the Broad Institute Clinical Research Sequencing Platform […]
Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome
Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39–3.79], p = 1.23103) and known, pathogenic CNVs (OR = 3.03 [1.85–5.07], p = 1.5 3 105). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6–156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3–45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.Rare-Copy-Number-Variants-in-NRXN1-and-CNTN6-_-Neuron.pdf
Developmental alterations in Huntington’s disease neural cells and pharmacological rescue in cells and mice
Nat Neurosci. 2017 May;20(5):648-660. doi: 10.1038/nn.4532. Epub 2017 Mar 20.
Neural cultures derived from Huntington’s disease (HD) patient-derived induced pluripotent stem cells were used for ‘omics’ analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium influx whose expression was decreased in HD cultures. One-third of gene changes were in pathways regulating neuronal development and maturation. When mapped to stages of mouse striatal development, the profiles aligned with earlier embryonic stages of neuronal differentiation. We observed a strong correlation between HD-related histone marks, gene expression and unique peak profiles associated with dysregulated genes, suggesting a coordinated epigenetic program. Treatment with isoxazole-9, which targets key dysregulated pathways, led to amelioration of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice. These data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeats over time.Developmental-alterations-in-Huntingtons-disease-neural-cells-and-pharmacological-rescue-in-cells-and-mice.pdf
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies
Nat Genet. 2017 Jan;49(1):36-45. doi: 10.1038/ng.3720. Epub 2016 Nov 14.
Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.Redin_NatGen_InPress.pdf
Identification of Underlying Genes
Genetic variants in CETP increase risk of intracerebral hemorrhage
Ann Neurol. 2016 Nov;80(5):730-740. doi: 10.1002/ana.24780. Epub 2016 Oct 19.
In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR]51.25, standard error [SE]50.06, p56.031024) with no heterogeneity across studies (I250%). This association was replicated in patients of European ancestry (p50.03). A genetic score of CETP variants found to increase HDL-C by _2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR51.86, SE50.13, p51.3931026). Interpretation: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted.Genetic-variants-in-CETP-increase-risk-of-intracerebral-hemorrhage.pdf
Dr. Wheeler received her Ph.D. in Molecular Genetics from the Imperial College of Science, Technology and Medicine in London and carried out postdoctoral training at Massachusetts General Hospital. Her research […]
Susan A. Slaugenhaupt
My research focuses on two neurological disorders, familial dysautonomia (FD) and mucolipidosis type IV (MLIV), as well as the common cardiac disorder mitral valve prolapse (MVP). Our work is focused […]
Dr. Jim Walker received his Ph.D. in Biochemistry from the University of Cambridge and carried out post-doctoral training at Massachusetts General Hospital. His research focuses on understanding the genetics and […]