Browsing by Author "Wang, Kai"

Now showing 1 - 4 of 4
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    Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.
    (PLoS Genet, 2009-06) Bucan, Maja; Abrahams, Brett S; Wang, Kai; Glessner, Joseph T; Herman, Edward I; Sonnenblick, Lisa I; Alvarez Retuerto, Ana I; Imielinski, Marcin; Hadley, Dexter; Bradfield, Jonathan P; Kim, Cecilia; Gidaya, Nicole B; Lindquist, Ingrid; Hutman, Ted; Sigman, Marian; Kustanovich, Vlad; Lajonchere, Clara M; Singleton, Andrew; Kim, Junhyong; Wassink, Thomas H; McMahon, William M; Owley, Thomas; Sweeney, John A; Coon, Hilary; Nurnberger, John I; Li, Mingyao; Cantor, Rita M; Minshew, Nancy J; Sutcliffe, James S; Cook, Edwin H; Dawson, Geraldine; Buxbaum, Joseph D; Grant, Struan FA; Schellenberg, Gerard D; Geschwind, Daniel H; Hakonarson, Hakon
    The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
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    Heuristics for Inventory Systems Based on Quadratic Approximation of L-Natural-Convex Value Functions
    (2014) Wang, Kai

    We propose an approximation scheme for single-product periodic-review inventory systems with L-natural-convex structure. We lay out three well-studied inventory models, namely the lost-sales system, the perishable inventory system, and the joint inventory-pricing problem. We approximate the value functions for these models by the class of L-natural-convex quadratic functions, through the technique of linear programming approach to approximate dynamic programming. A series of heuristics are derived based on the quadratic approximation, and their performances are evaluated by comparison with existing heuristics. We present the numerical results and show that our heuristics outperform the benchmarks for majority of cases and scale well with long lead times. In this dissertation we also discuss the alternative strategies we have tried but with unsatisfactory result.

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    Rare variants create synthetic genome-wide associations.
    (PLoS Biol, 2010-01-26) Dickson, Samuel P; Wang, Kai; Krantz, Ian; Hakonarson, Hakon; Goldstein, David B
    Genome-wide association studies (GWAS) have now identified at least 2,000 common variants that appear associated with common diseases or related traits (http://www.genome.gov/gwastudies), hundreds of which have been convincingly replicated. It is generally thought that the associated markers reflect the effect of a nearby common (minor allele frequency >0.05) causal site, which is associated with the marker, leading to extensive resequencing efforts to find causal sites. We propose as an alternative explanation that variants much less common than the associated one may create "synthetic associations" by occurring, stochastically, more often in association with one of the alleles at the common site versus the other allele. Although synthetic associations are an obvious theoretical possibility, they have never been systematically explored as a possible explanation for GWAS findings. Here, we use simple computer simulations to show the conditions under which such synthetic associations will arise and how they may be recognized. We show that they are not only possible, but inevitable, and that under simple but reasonable genetic models, they are likely to account for or contribute to many of the recently identified signals reported in genome-wide association studies. We also illustrate the behavior of synthetic associations in real datasets by showing that rare causal mutations responsible for both hearing loss and sickle cell anemia create genome-wide significant synthetic associations, in the latter case extending over a 2.5-Mb interval encompassing scores of "blocks" of associated variants. In conclusion, uncommon or rare genetic variants can easily create synthetic associations that are credited to common variants, and this possibility requires careful consideration in the interpretation and follow up of GWAS signals.
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    The PsychENCODE project.
    (Nat Neurosci, 2015-12) PsychENCODE Consortium; Akbarian, Schahram; Liu, Chunyu; Knowles, James A; Vaccarino, Flora M; Farnham, Peggy J; Crawford, Gregory E; Jaffe, Andrew E; Pinto, Dalila; Dracheva, Stella; Geschwind, Daniel H; Mill, Jonathan; Nairn, Angus C; Abyzov, Alexej; Pochareddy, Sirisha; Prabhakar, Shyam; Weissman, Sherman; Sullivan, Patrick F; State, Matthew W; Weng, Zhiping; Peters, Mette A; White, Kevin P; Gerstein, Mark B; Amiri, Anahita; Armoskus, Chris; Ashley-Koch, Allison E; Bae, Taejeong; Beckel-Mitchener, Andrea; Berman, Benjamin P; Coetzee, Gerhard A; Coppola, Gianfilippo; Francoeur, Nancy; Fromer, Menachem; Gao, Robert; Grennan, Kay; Herstein, Jennifer; Kavanagh, David H; Ivanov, Nikolay A; Jiang, Yan; Kitchen, Robert R; Kozlenkov, Alexey; Kundakovic, Marija; Li, Mingfeng; Li, Zhen; Liu, Shuang; Mangravite, Lara M; Mangravite, Lara M; Mattei, Eugenio; Markenscoff-Papadimitriou, Eirene; Navarro, Fábio CP; North, Nicole; Omberg, Larsson; Panchision, David; Parikshak, Neelroop; Poschmann, Jeremie; Price, Amanda J; Purcaro, Michael; Reddy, Timothy E; Roussos, Panos; Schreiner, Shannon; Scuderi, Soraya; Sebra, Robert; Shibata, Mikihito; Shieh, Annie W; Skarica, Mario; Sun, Wenjie; Swarup, Vivek; Thomas, Amber; Tsuji, Junko; van Bakel, Harm; Wang, Daifeng; Wang, Yongjun; Wang, Kai; Werling, Donna M; Willsey, A Jeremy; Witt, Heather; Won, Hyejung; Wong, Chloe CY; Wray, Gregory A; Wu, Emily Y; Xu, Xuming; Yao, Lijing; Senthil, Geetha; Lehner, Thomas; Sklar, Pamela; Sestan, Nenad