A Method for Gene‐Based Pathway Analysis Using Genomewide Association Study Summary Statistics Reveals Nine New Type 1 Diabetes Associations. Issue 8 (4th November 2014)

• Record Type: Journal Article
• Authors: Evangelou, Marina; Smyth, Deborah J.; Fortune, Mary D.; Burren, Oliver S.; Walker, Neil M.; Guo, Hui; Onengut‐Gumuscu, Suna; Chen, Wei‐Min; Concannon, Patrick; Rich, Stephen S.; Todd, John A.; Wallace, Chris
• Is Part Of: Genetic epidemiology. Volume 38:Issue 8(2014)
• Page Start: 661
• Page End: 670
• Publication Date: 2014-11-04
• Subjects: Genetic epidemiology -- Periodicals; Heredity -- Periodicals; Medical geography -- Periodicals; 614
• DOI: 10.1002/gepi.21853
• Languages: English
• ISSNs: 0741-0395

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>Pathway analysis can complement point‐wise single nucleotide polymorphism (SNP) analysis in exploring genomewide association study (GWAS) data to identify specific disease‐associated genes that can be candidate causal genes. We propose a straightforward methodology that can be used for conducting a gene‐based pathway analysis using summary GWAS statistics in combination with widely available reference genotype data. We used this method to perform a gene‐based pathway analysis of a type 1 diabetes (T1D) meta‐analysis GWAS (of 7, 514 cases and 9, 045 controls). An important feature of the conducted analysis is the removal of the major histocompatibility complex gene region, the major genetic risk factor for T1D. Thirty‐one of the 1, 583 (2%) tested pathways were identified to be enriched for association with T1D at a 5% false discovery rate. We analyzed these 31 pathways and their genes to identify SNPs in or near these pathway genes that showed potentially novel association with T1D and attempted to replicate the association of 22 SNPs in additional samples. Replication <italic>P</italic>‐values were skewed (<inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr422z" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0003" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>9.85</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>11</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>) with 12 of the 22 SNPs showing <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr4242" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0004" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo><</mml:mo><mml:mn>0.05</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>. Support, including replication evidence, was obtained for nine T1D associated variants in genes <italic>ITGB7</italic> (rs11170466, <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr41x7" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0005" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>7.86</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>9</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>), <italic>NRP1</italic> (rs722988, <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr421d" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0006" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>4.88</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>8</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>), <italic>BAD</italic> (rs694739, <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr41tk" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0007" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>2.37</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>7</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>), <italic>CTSB</italic> (rs1296023, <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr41v4" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0008" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>2.79</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>7</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>), <italic>FYN</italic> (rs11964650, <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr41s1" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0009" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>5.60</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>7</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>), <italic>UBE2G1</italic> (rs9906760, <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr43qz" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0010" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>5.08</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>7</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>), <italic>MAP3K14</italic> (rs17759555, <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr43s2" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0011" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>9.67</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>7</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>), <italic>ITGB1</italic> (rs1557150, <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr43v5" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0012" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>1.93</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>6</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>), and <italic>IL7R</italic> (rs1445898, <inline-formula><alternatives><inline-graphic mimetype="image" xlink:href="ark:/27927/pgh2cnr43wq" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math display="inline" altimg="urn:x-wiley:07410395:media:gepi21853:gepi21853-math-0013" overflow="scroll" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>2.76</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mrow><mml:mo>−</mml:mo><mml:mn>6</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>). The proposed methodology can be applied to other GWAS datasets for which only summary level data are available.</p> </abstract>