Comparison of multimarker logistic regression models, with application to a genomewide scan of schizophrenia

Wason, James M. S.; Dudbridge, Frank
January 2010
BMC Genetics;2010, Vol. 11, p80
Academic Journal
Background: Genome-wide association studies (GWAS) are a widely used study design for detecting genetic causes of complex diseases. Current studies provide good coverage of common causal SNPs, but not rare ones. A popular method to detect rare causal variants is haplotype testing. A disadvantage of this approach is that many parameters are estimated simultaneously, which can mean a loss of power and slower fitting to large datasets. Haplotype testing effectively tests both the allele frequencies and the linkage disequilibrium (LD) structure of the data. LD has previously been shown to be mostly attributable to LD between adjacent SNPs. We propose a generalised linear model (GLM) which models the effects of each SNP in a region as well as the statistical interactions between adjacent pairs. This is compared to two other commonly used multimarker GLMs: one with a main-effect parameter for each SNP; one with a parameter for each haplotype. Results: We show the haplotype model has higher power for rare untyped causal SNPs, the main-effects model has higher power for common untyped causal SNPs, and the proposed model generally has power in between the two others. We show that the relative power of the three methods is dependent on the number of marker haplotypes the causal allele is present on, which depends on the age of the mutation. Except in the case of a common causal variant in high LD with markers, all three multimarker models are superior in power to single-SNP tests. Including the adjacent statistical interactions results in lower inflation in test statistics when a realistic level of population stratification is present in a dataset. Using the multimarker models, we analyse data from the Molecular Genetics of Schizophrenia study. The multimarker models find potential associations that are not found by single-SNP tests. However, multimarker models also require stricter control of data quality since biases can have a larger inflationary effect on multimarker test statistics than on single-SNP test statistics. Conclusions: Analysing a GWAS with multimarker models can yield candidate regions which may contain rare untyped causal variants. This is useful for increasing prior odds of association in future whole-genome sequence analyses.


Related Articles

  • A Scale-Corrected Comparison of Linkage Disequilibrium Levels between Genic and Non-Genic Regions. Berger, Swetlana; Schlather, Martin; de los Campos, Gustavo; Weigend, Steffen; Preisinger, Rudolf; Erbe, Malena; Simianer, Henner // PLoS ONE;10/30/2015, Vol. 10 Issue 10, p1 

    The understanding of non-random association between loci, termed linkage disequilibrium (LD), plays a central role in genomic research. Since causal mutations are generally not included in genomic marker data, LD between those and available markers is essential for capturing the effects of...

  • Purging Deleterious Mutations under Self Fertilization: Paradoxical Recovery in Fitness with Increasing Mutation Rate in Caenorhabditis elegans. Morran, Levi T.; Ohdera, Aki H.; Phillips, Patrick C. // PLoS ONE;2010, Vol. 5 Issue 12, p1 

    Background: The accumulation of deleterious mutations can drastically reduce population mean fitness. Self-fertilization is thought to be an effective means of purging deleterious mutations. However, widespread linkage disequilibrium generated and maintained by self-fertilization is predicted to...

  • A Recombination Hotspot in a Schizophrenia-Associated Region of GABRB2. Siu-Kin Ng; Wing-Sze Lo; Pun, Frank W.; Cunyou Zhao; Zhiliang Yu; Jianhuan Chen; Ka-Lok Tong; Zhiwen Xu; Shui-Ying Tsang; Qiang Yang; Weichuan Yu; Nimgaonkar, Vishwajit; Stöber, Gerald; Harano, Mutsuo; Hong Xue // PLoS ONE;2010, Vol. 5 Issue 3, p1 

    Background: Schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the β2 subunit of GABAA receptors, within a segment of 3,551 bp harboring twenty-nine single...

  • Filaggrin Gene Mutation c.3321delA Is Associated with Various Clinical Features of Atopic Dermatitis in the Chinese Han Population. Meng, Li; Wang, Li; Tang, Huayang; Tang, Xianfa; Jiang, Xiaoyun; Zhao, Jinhua; Gao, Jing; Li, Bing; Fu, Xuhui; Chen, Yan; Yao, Weiyi; Zhan, Wenying; Wu, Bo; Duan, Dawei; Shen, Changbing; Cheng, Hui; Zuo, Xianbo; Yang, Sen; Sun, Liangdan; Zhang, Xuejun // PLoS ONE;May2014, Vol. 9 Issue 5, p1 

    Background: We confirmed that the filaggrin gene mutation c.3321delA is associated with atopic dermatitis in our previous genome wide association study of the Chinese Han population. c.3321delA is the most common filaggrin gene mutation in Chinese atopic dermatitis patients but is not present in...

  • Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects. Bergamaschi, Laura; Ban, Maria; Barizzone, Nadia; Leone, Maurizio; Ferrante, Daniela; Fasano, Maria Edvige; Guerini, Franca R.; Corrado, Lucia; Naldi, Paola; Dametto, Ennia; Agliardi, Cristina; Salvetti, Marco; Mechelli, Rosella; Galimberti, Daniela; Scarpini, Elio; Cavalla, Paola; Bargiggia, Valeria; Caputo, Domenico; Cordera, Susanna; Monaco, Francesco // Journal of Medical Genetics;Jul2011, Vol. 48 Issue 7, p485 

    Background: The association of HLA A*02 with multiple sclerosis (MS) was recently confirmed by the authors, and it was observed that the combined presence of HLA Cw*05 significantly enhanced (threefold) the protective effect of HLA A*02. Objectives and methods: Since A*02-Cw*05 is carried by two...

  • Finding disease genes: a fast and flexible approach for analyzing high-throughput data. Stewart, William C. L.; Drill, Esther N.; Greenberg, David A. // European Journal of Human Genetics;Oct2011, Vol. 19 Issue 10, p1090 

    Linkage disequilibrium (LD) is the non-random distribution of alleles across the genome, and it can create serious problems for modern linkage studies. In particular, computational feasibility is often obtained at the expense of power, precision, and/or accuracy. In our new approach, we combine...

  • Utilizing linkage disequilibrium information from Indian Genome Variation Database for mapping mutations: SCA12 case study. BAHL, SAMIRA; AHMED, IKHLAK; MUKERJI, MITALI // Journal of Genetics;Apr2009, Vol. 88 Issue 1, p55 

    Stratification in heterogeneous populations poses an enormous challenge in linkage disequilibrium (LD) based identification of causal loci using surrogate markers. In this study, we demonstrate the enormous potential of endogamous Indian populations for mapping mutations in candidate genes using...

  • Tag-SNP analysis of the GFI1-EVI5-RPL5-FAM69 risk locus for multiple sclerosis. Alcina, Antonio; Fernández, Óscar; Gonzalez, Juan Ramón; Catalá-Rabasa, Antonio; Fedetz, María; Ndagire, Dorothy; Leyva, Laura; Guerrero, Miguel; Arnal, Carmen; Delgado, Concepción; Lucas, Miguel; Izquierdo, Guillermo; Matesanz, Fuencisla // European Journal of Human Genetics;Jul2010, Vol. 18 Issue 7, p827 

    A recent genome-wide association study conducted by the International Multiple Sclerosis Genetic Consortium (IMSGC) identified, among others, a number of putative multiple sclerosis (MS) susceptibility variants at position 1p22. Twenty-one SNPs positively associated with MS were located at the...

  • The Interaction between Coagulation Factor 2 Receptor and Interleukin 6 Haplotypes Increases the Risk of Myocardial Infarction in Men. Gigante, Bruna; Bennet, Anna M.; Leander, Karin; Vikström, Max; de Faire, Ulf // PLoS ONE;2010, Vol. 5 Issue 6, p1 

    The aim of the study was to investigate if the interaction between the coagulation factor 2 receptor (F2R) and the interleukin 6 (IL6) haplotypes modulates the risk of myocardial infarction (MI) in the Stockholm Heart Epidemiology Program (SHEEP). Seven SNPs at the F2R locus and three SNPs at...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics