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Evidence for polygenic susceptibility to multiple sclerosis--the shape of things to come.

ABSTRACT: It is well established that the risk of developing multiple sclerosis is substantially increased in the relatives of affected individuals and that most of this increase is genetically determined. The observed pattern of familial recurrence risk has long suggested that multiple variants are involved, but it has proven difficult to identify individual risk variants and little has been established about the genetic architecture underlying susceptibility. By using data from two independent genome-wide association studies (GWAS), we demonstrate that a substantial proportion of the thousands of variants that individually fail to show statistically significant evidence of association have allele frequencies in cases that are skewed away from the null distribution through the effects of multiple as-yet-unidentified risk loci. The collective effect of 12,627 SNPs with Cochran-Mantel-Haenszel test (p < 0.2) in our discovery GWAS set optimally explains approximately 3% of the variance in MS risk in our independent target GWAS set, estimated by Nagelkerke's pseudo-R(2). This model has a highly significant fit (p = 9.90E-19). These results statistically demonstrate a polygenic component to MS susceptibility and suggest that the risk alleles identified to date represent just the tip of an iceberg of risk variants likely to include hundreds of modest effects and possibly thousands of very small effects.

SUBMITTER: International Multiple Sclerosis Genetics Consortium (IMSGC)

PROVIDER: S-EPMC2850422 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Evidence for polygenic susceptibility to multiple sclerosis--the shape of things to come.

Bush William S WS Sawcer Stephen J SJ de Jager Philip L PL Oksenberg Jorge R JR McCauley Jacob L JL Pericak-Vance Margaret A MA Haines Jonathan L JL

American journal of human genetics 20100401 4

It is well established that the risk of developing multiple sclerosis is substantially increased in the relatives of affected individuals and that most of this increase is genetically determined. The observed pattern of familial recurrence risk has long suggested that multiple variants are involved, but it has proven difficult to identify individual risk variants and little has been established about the genetic architecture underlying susceptibility. By using data from two independent genome-wi ...[more]

PMID: 20362272

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Project description:Historically, time preferences are modelled by assuming constant discounting, which implies a constant level of impatience. The prevailing empirical finding, however, is decreasing impatience (DI), meaning that levels of impatience decrease over time. Theoretically, such changes in impatience are crucial to understand behavior and self-control problems. Very few methods exist to measure DI without being restricted to or confounded by certain assumptions about the discounting function or utility curve. One such measure is the recently introduced DI-index, which has been applied to both monetary and health outcomes. The DI-index quantifies the deviation from constant impatience and is flexible enough to capture both increasing and decreasing impatience. In this study, we apply the DI-index to measure impatience for health outcomes in a reference-dependent framework. That is, we measure impatience for both health gains and health losses compared to a reference-point, in individual and societal settings, using a within-subjects design (n = 98). We allowed for both positive and negative discounting, since negative discounting has been observed for losses (i.e. preferring to incur losses earlier rather than later) in earlier work. To capture changes in time inconsistency when subjects show negative discounting (i.e. patience), we modify the DI-index to a decreasing (im)patience (DIP)-index, which can be applied without loss of generality. As in earlier work, we observe large heterogeneity in time consistency; i.e., a mix of decreasing, increasing and constant (im)patience. Across all DIP-indices elicited, increasing impatience was the modal preference for those satisfying impatience, and decreasing patience for those satisfying patience. No systematic differences were observed between health gains and losses or between societal and individual outcomes. This suggests that for health outcomes both patient and impatient individuals assign more importance to time differences delayed further in the future.

Project description:ObjectiveTo explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans.BackgroundRecently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB1*15:01~HLA-DQB1*06:02, and HLA-DRB1*03:01~ HLA-DQB1*02:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of these newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort.Design/methodsThe African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational "Be the Match" registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms.ResultsOf the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB1*15:03~DQB1*06:02~a36 haplotype and three carried the DRB1*15:01~DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)-similar to that observed in the WTCCC (OR = 3.25; p<10-168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)-again, similar to the WTCCC (OR = 2.2; p<10-38). Moreover, four African haplotypes were "protective" relative to a neutral reference, to three European CEHs, and also to the five other African CEHs.ConclusionsThe common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were "protective"-perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.

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Evidence for polygenic susceptibility to multiple sclerosis--the shape of things to come.

Publications

Evidence for polygenic susceptibility to multiple sclerosis--the shape of things to come.

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