Browsing by Author "Doheny, Kimberly"

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    Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm
    (PLoS, 2015-03-24) Farlow, Janice L.; Lin, Hai; Sauerbeck, Laura; Lai, Dongbing; Koller, Daniel L.; Pugh, Elizabeth; Hetrick, Kurt; Ling, Hua; Kleinloog, Rachel; van der Vlies, Peter; Deelen, Patrick; Swertz, Morris A.; Verweij, Bon H.; Regli, Luca; Rinkel, Gabriel J.E.; Ruigrok, Ynte M.; Doheny, Kimberly; Liu, Yunlong; Broderick, Joseph; Foroud, Tatiana; Department of Medical and Molecular Genetics, IU School of Medicine
    Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.
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    PRIORITIZATION OF RESULTS FROM WHOLE EXOME SEQUENCING IN FAMILIAL INTRACRANIAL ANEURYSM
    (Office of the Vice Chancellor for Research, 2012-04-13) Farlow, Janice L.; Lin, Hai; Hetrick, Kurt; Ling, Hua; Lai, Dongbing; Sauerbeck, Laura; Woo, Daniel; Langefeld, Carl; Brown, Robert; Pugh, Elizabeth; Doheny, Kimberly; Liu, Yunlong; Foroud, Tatiana; Broderick, Joseph; Foroud, Tatiana
    Whole exome sequencing (WES) is an innovative approach to identifying rare variants associated with disease; however, reducing the large number of variants to a useful set of candidate genes is challenging. We developed a ranking system utilizing data from a previous genome-wide linkage analysis and various bioinformatics databases to prioritize the results of WES from families having multiple members with intracranial aneurysms. WES was performed in 35 affected individuals and 10 unaffected individ-uals across 7 families. All samples were genotyped (Illumina® OmniExpress) and sequenced (Agilent© SureSelect™ 50Mb Human All Exon Kit). Linkage analysis (Illumina 6K) was previously performed using autosomal domi-nant/recessive modes of inheritance. Application of quality filters resulted in 91,659 single nucleotide variants (SNVs). Nonsynonymous SNVs within an exon having an allele frequency of <3% were retained. Further filtering was performed based on Mendelian in-heritance (autosomal dominant or recessive). A ranking system prioritized retained variants based on the inheritance pattern specific to each family, occurrence in multiple families, relation to pathways and genes of interest, degree of penetrance, presence within a linkage peak, and whether the re-sultant proteins were predicted to be deleterious. Out of a 9-point score, 292 variants in 190 genes received scores of at least 5. Of these, 14 variants in 10 genes met the majority of prioritization criteria by achieving scores of over 7. While several WES studies have been successful at identifying genes im-portant to rare diseases, few have examined how to produce a list of candi-date genes contributing to a complex disease from WES data. We show that a ranking system that combines WES with bioinformatics resources and link-age data is a powerful approach to prioritize candidate genes for a complex disease like familial intracranial aneurysms. Subsequent studies are required to validate the utility of this approach.
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    Whole-Exome Sequencing in Familial Parkinson Disease
    (The JAMA Network, 2016-01) Farlow, Janice L.; Robak, Laurie A.; Hetrick, Kurt; Bowling, Kevin; Boerwinkle, Eric; Coban-Akdemir, Zeynep H.; Gambin, Tomasz; Gibbs, Richard A.; Gu, Shen; Jain, Preti; Jankovic, Joseph; Jhangiani, Shalini; Kaw, Kaveeta; Lai, Dongbing; Lin, Hai; Ling, Hua; Liu, Yunlong; Lupski, James R.; Muzny, Donna; Porter, Paula; Pugh, Elizabeth; White, Janson; Doheny, Kimberly; Myers, Richard M.; Shulman, Joshua M.; Foroud, Tatiana; Department of Medical and Molecular Genetics, IU School of Medicine
    IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.