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2014

Han B, Kang EY, Raychaudhuri S, Bakker P, Eskin E. Fast pairwise IBD association testing in genome-wide association studies. Bioinformatics. 2014;30(2):206–13.
Publisher's Version
MOTIVATION: Recently, investigators have proposed state-of-the-art Identity-by-descent (IBD) mapping methods to detect IBD segments between purportedly unrelated individuals. The IBD information can then be used for association testing in genetic association studies. One approach for this IBD association testing strategy is to test for excessive IBD between pairs of cases ('pairwise method'). However, this approach is inefficient because it requires a large number of permutations. Moreover, a limited number of permutations define a lower bound for P-values, which makes fine-mapping of associated regions difficult because, in practice, a much larger genomic region is implicated than the region that is actually associated. RESULTS: In this article, we introduce a new pairwise method 'Fast-Pairwise'. Fast-Pairwise uses importance sampling to improve efficiency and enable approximation of extremely small P-values. Fast-Pairwise method takes only days to complete a genome-wide scan. In the application to the WTCCC type 1 diabetes data, Fast-Pairwise successfully fine-maps a known human leukocyte antigen gene that is known to cause the disease. AVAILABILITY: Fast-Pairwise is publicly available at: http://genetics.cs.ucla.edu/graphibd.
Dunstan S, Hue NT, Han B, Li Z, Tram TTB, Sim KS, Parry C, Chinh NT, Vinh H, Lan NPH, Thieu NTV, Vinh PV, Koirala S, Dongol S, Arjyal A, Karkey A, Shilpakar O, Dolecek C, Foo JN, Phuong LT, Lanh MN, Do T, Aung T, Hon DN, Teo YY, Hibberd M, Anders K, Okada Y, Raychaudhuri S, Simmons C, Baker S, Bakker P, Basnyat B, Hien TT, Farrar J, Khor CC. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat Genet. 2014;46(12):1333–6.
Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C(1). We conducted a genome-wide association study of 432 individuals with blood culture-confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10(-10)), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10(-11)) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.
Roussos P, Mitchell A, Voloudakis G, Fullard J, Pothula V, Tsang J, Stahl E, Georgakopoulos A, Ruderfer D, Charney A, Okada Y, Siminovitch K, Worthington J, Padyukov L, Klareskog L, Gregersen P, Plenge R, Raychaudhuri S, Fromer M, Purcell S, Brennand K, Robakis N, Schadt E, Akbarian S, Sklar P. A role for noncoding variation in schizophrenia. Cell Rep. 2014;9(4):1417–29.
Publisher's Version
A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.
Gusev A, Lee H, Trynka G, Finucane H, Vilhjálmsson B, Xu H, Zang C, Ripke S, Bulik-Sullivan B, Stahl E, Consortium SWGPG, SWE-SCZ Consortium, Kähler A, Hultman C, Purcell S, McCarroll S, Daly M, Pasaniuc B, Sullivan P, Neale B, Wray N, Raychaudhuri S, Price A, Consortium SWGPG, SWE-SCZ Consortium. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am J Hum Genet. 2014;95(5):535–52.
Publisher's Version
Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg(2) from imputed SNPs (5.1× enrichment; p = 3.7 × 10(-17)) and 38% (SE = 4%) of hg(2) from genotyped SNPs (1.6× enrichment, p = 1.0 × 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg(2) despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.
Lim E, Liu Y, Chan Y, Tiinamaija T, Käräjämäki A, Madsen E, Go-T2D Consortium, Altshuler D, Raychaudhuri S, Groop L, Flannick J, Hirschhorn J, Katsanis N, Daly M. A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity. Am J Hum Genet. 2014;95(5):509–20.
Publisher's Version
Rare-variant association studies in common, complex diseases are customarily conducted under an additive risk model in both single-variant and burden testing. Here, we describe a method to improve detection of rare recessive variants in complex diseases termed RAFT (recessive-allele-frequency-based test). We found that RAFT outperforms existing approaches when the variant influences disease risk in a recessive manner on simulated data. We then applied our method to 1,791 Finnish individuals with type 2 diabetes (T2D) and 2,657 matched control subjects. In BBS10, we discovered a rare variant (c.1189A>G [p.Ile397Val]; rs202042386) that confers risk of T2D in a recessive state (p = 1.38 × 10(-6)) and would be missed by conventional methods. Testing of this variant in an established in vivo zebrafish model confirmed the variant to be pathogenic. Taken together, these data suggest that RAFT can effectively reveal rare recessive contributions to complex diseases overlooked by conventional association tests.
Yu Y, Triebwasser M, Wong E, Schramm E, Thomas B, Reynolds R, Mardis E, Atkinson J, Daly M, Raychaudhuri S, Kavanagh D, Seddon J. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum Mol Genet. 2014;23(19):5283–93.
Publisher's Version
We sequenced the whole exome of 35 cases and 7 controls from 9 age-related macular degeneration (AMD) families in whom known common genetic risk alleles could not explain their high disease burden and/or their early-onset advanced disease. Two families harbored novel rare mutations in CFH (R53C and D90G). R53C segregates perfectly with AMD in 11 cases (heterozygous) and 1 elderly control (reference allele) (LOD = 5.07, P = 6.7 × 10(-7)). In an independent cohort, 4 out of 1676 cases but none of the 745 examined controls or 4300 NHBLI Exome Sequencing Project (ESP) samples carried the R53C mutation (P = 0.0039). In another family of six siblings, D90G similarly segregated with AMD in five cases and one control (LOD = 1.22, P = 0.009). No other sample in our large cohort or the ESP had this mutation. Functional studies demonstrated that R53C decreased the ability of FH to perform decay accelerating activity. D90G exhibited a decrease in cofactor-mediated inactivation. Both of these changes would lead to a loss of regulatory activity, resulting in excessive alternative pathway activation. This study represents an initial application of the whole-exome strategy to families with early-onset AMD. It successfully identified high impact alleles leading to clearer functional insight into AMD etiopathogenesis.
Schramm E, Clark S, Triebwasser M, Raychaudhuri S, Seddon J, Atkinson J. Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol Immunol. 2014;61(2):118–25.
Publisher's Version
Age-related macular degeneration (AMD) is a major cause of visual impairment in the western world. It is characterized by the presence of lipoproteinaceous deposits (drusen) in the inner layers of the retina. Immunohistochemistry studies identified deposition of complement proteins in the drusen as well as in the choroid. In the last decade, genetic studies have linked both common and rare variants in genes of the complement system to increased risk of development of AMD. Here, we review the variants described to date and discuss the functional implications of dysregulation of the alternative pathway of complement in AMD.
Pillai NE, Okada Y, Saw WY, Ong RTH, Wang X, Tantoso E, Xu W, Peterson T, Bielawny T, Ali M, Tay KY, Poh WT, Tan LWL, Koo SH, Lim WY, Soong R, Wenk M, Raychaudhuri S, Little P, Plummer F, Lee E, Chia KS, Luo M, Bakker P, Teo YY. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations. Hum Mol Genet. 2014;23(16):4443–51.
The major histocompatibility complex (MHC) containing the classical human leukocyte antigen (HLA) Class I and Class II genes is among the most polymorphic and diverse regions in the human genome. Despite the clinical importance of identifying the HLA types, very few databases jointly characterize densely genotyped single nucleotide polymorphisms (SNPs) and HLA alleles in the same samples. To date, the HapMap presents the only public resource that provides a SNP reference panel for predicting HLA alleles, constructed with four collections of individuals of north-western European, northern Han Chinese, cosmopolitan Japanese and Yoruba Nigerian ancestry. Owing to complex patterns of linkage disequilibrium in this region, it is unclear whether the HapMap reference panels can be appropriately utilized for other populations. Here, we describe a public resource for the Singapore Genome Variation Project with: (i) dense genotyping across ∼ 9000 SNPs in the MHC; (ii) four-digit HLA typing for eight Class I and Class II loci, in 96 southern Han Chinese, 89 Southeast Asian Malays and 83 Tamil Indians. This resource provides population estimates of the frequencies of HLA alleles at these eight loci in the three population groups, particularly for HLA-DPA1 and HLA-DPB1 that were not assayed in HapMap. Comparing between population-specific reference panels and a cosmopolitan panel created from all four HapMap populations, we demonstrate that more accurate imputation is obtained with population-specific panels than with the cosmopolitan panel, especially for the Malays and Indians but even when imputing between northern and southern Han Chinese. As with SNP imputation, common HLA alleles were imputed with greater accuracy than low-frequency variants.
Arking D, Pulit S, Crotti L, Harst P, Munroe P, Koopmann T, Sotoodehnia N, Rossin E, Morley M, Wang X, Johnson A, Lundby A, Gudbjartsson D, Noseworthy P, Eijgelsheim M, Bradford Y, Tarasov K, Dörr M, Müller-Nurasyid M, Lahtinen A, Nolte I, Smith AV, Bis J, Isaacs A, Newhouse S, Evans D, Post W, Waggott D, Lyytikäinen LP, Hicks A, Eisele L, Ellinghaus D, Hayward C, Navarro P, Ulivi S, Tanaka T, Tester D, Chatel S, Gustafsson S, Kumari M, Morris R, Naluai Å, Padmanabhan S, Kluttig A, Strohmer B, Panayiotou A, Torres M, Knoflach M, Hubacek J, Slowikowski K, Raychaudhuri S, Kumar R, Harris T, Launer L, Shuldiner A, Alonso A, Bader J, Ehret G, Huang H, Kao L, Strait J, Macfarlane P, Brown M, Caulfield M, Samani N, Kronenberg F, Willeit J, CARe Consortium, COGENT Consortium, Smith G, Greiser K, Meyer Zu Schwabedissen H, Werdan K, Carella M, Zelante L, Heckbert S, Psaty B, Rotter J, Kolcic I, Polašek O, Wright A, Griffin M, Daly M, DCCT/EDIC, Arnar D, Hólm H, Thorsteinsdottir U, eMERGE Consortium, Denny J, Roden D, Zuvich R, Emilsson V, Plump A, Larson M, O’Donnell C, Yin X, Bobbo M, D’Adamo A, Iorio A, Sinagra G, Carracedo A, Cummings S, Nalls M, Jula A, Kontula K, Marjamaa A, Oikarinen L, Perola M, Porthan K, Erbel R, Hoffmann P, Jöckel KH, Kälsch H, Nöthen M, HRGEN Consortium, Hoed M, Loos R, Thelle D, Gieger C, Meitinger T, Perz S, Peters A, Prucha H, Sinner M, Waldenberger M, Boer R, Franke L, Vleuten P, Beckmann BM, Martens E, Bardai A, Hofman N, Wilde A, Behr E, Dalageorgou C, Giudicessi J, Medeiros-Domingo A, Barc J, Kyndt F, Probst V, Ghidoni A, Insolia R, Hamilton R, Scherer S, Brandimarto J, Margulies K, Moravec C, Greco M F, Fuchsberger C, O’Connell J, Lee W, Watt G, Campbell H, Wild S, El Mokhtari N, Frey N, Asselbergs F, Mateo Leach I, Navis G, Berg M, Veldhuisen D, Kellis M, Krijthe B, Franco O, Hofman A, Kors J, Uitterlinden A, Witteman J, Kedenko L, Lamina C, Oostra B, Abecasis G, Lakatta E, Mulas A, Orrú M, Schlessinger D, Uda M, Markus M, Völker U, Snieder H, Spector T, Ärnlöv J, Lind L, Sundström J, Syvänen AC, Kivimaki M, Kähönen M, Mononen N, Raitakari O, Viikari J, Adamkova V, Kiechl S, Brion M, Nicolaides A, Paulweber B, Haerting J, Dominiczak A, Nyberg F, Whincup P, Hingorani A, Schott JJ, Bezzina C, Ingelsson E, Ferrucci L, Gasparini P, Wilson J, Rudan I, Franke A, Mühleisen T, Pramstaller P, Lehtimäki T, Paterson A, Parsa A, Liu Y, Duijn C, Siscovick D, Gudnason V, Jamshidi Y, Salomaa V, Felix S, Sanna S, Ritchie M, Stricker B, Stefansson K, Boyer L, Cappola T, Olsen J, Lage K, Schwartz P, Kääb S, Chakravarti A, Ackerman M, Pfeufer A, Bakker P, Newton-Cheh C. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet. 2014;46(8):826–36.
Publisher's Version
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
Liao K, Diogo D, Cui J, Cai T, Okada Y, Gainer V, Murphy S, Gupta N, Mirel D, Ananthakrishnan A, Szolovits P, Shaw S, Raychaudhuri S, Churchill S, Kohane I, Karlson E, Plenge R. Association between low density lipoprotein and rheumatoid arthritis genetic factors with low density lipoprotein levels in rheumatoid arthritis and non-rheumatoid arthritis controls. Ann Rheum Dis. 2014;73(6):1170–5.
Publisher's Version
OBJECTIVES: While genetic determinants of low density lipoprotein (LDL) cholesterol levels are well characterised in the general population, they are understudied in rheumatoid arthritis (RA). Our objective was to determine the association of established LDL and RA genetic alleles with LDL levels in RA cases compared with non-RA controls. METHODS: Using data from electronic medical records, we linked validated RA cases and non-RA controls to discarded blood samples. For each individual, we extracted data on: first LDL measurement, age, gender and year of LDL measurement. We genotyped subjects for 11 LDL and 44 non-HLA RA alleles, and calculated RA and LDL genetic risk scores (GRS). We tested the association between each GRS and LDL level using multivariate linear regression models adjusted for age, gender, year of LDL measurement and RA status. RESULTS: Among 567 RA cases and 979 controls, 80% were female and mean age at the first LDL measurement was 55 years. RA cases had significantly lower mean LDL levels than controls (117.2 vs 125.6 mg/dl, respectively, p<0.0001). Each unit increase in LDL GRS was associated with 0.8 mg/dl higher LDL levels in both RA cases and controls (p=3.0×10(-7)). Each unit increase in RA GRS was associated with 4.3 mg/dl lower LDL levels in both groups (p=0.01). CONCLUSIONS: LDL alleles were associated with higher LDL levels in RA. RA alleles were associated with lower LDL levels in both RA cases and controls. As RA cases carry more RA alleles, these findings suggest a genetic basis for epidemiological observations of lower LDL levels in RA.