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Expand Figure 1Manhattan plot of genome-widelog(10p-values for association with AAT serum level.

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The strength of this study is that it combines the report of a GWAS on AAT serum levels with meta-analyses of the associations of some of the GWAS top variants with lung functionThe effects of the underlying functional variants are thoroughly investigated resulting in the hitherto largest meta-analysis of PI S and Z on FEV1 in ever-smokersAscertainment and study design of the many participating studies were sufficiently diverse to informatively address heterogeneity in association of common and rarer variants in the SERPINA gene cluster with lung functionThe strength of the discovery sample is the population-based study design and the detailed characterization of the participantsSexage and smoking are important modifiers of AAT blood levels in the general population43and were included in all regression modelsMore refined smoking variables covering smoking intensity were not included as this information is less complete than smoking status in SAPALDIA and would lower the sample sizeBy excluding samples with elevated hs-CRP values we avoided the masking of AAT deficiencies due to a chronic or acute inflammationOn the methodological sideconditional analysis is a well-established tool for identifying independent signals within a certain locus384950Furthermore1000G imputation was able to point to the causal variant demonstrating its reliability to correctly assign alleles close to the 1MAF threshold.

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AffiliationDepartment of Epidemiology and BiostatisticsImperial College LondonLondonUnited Kingdom.

SNPs reaching genome-wide significance are shown in greenThey all belong to the SERPINA gene cluster.

AffiliationDivision of Pulmonary MedicineUniversity Hospital of GenevaGenevaSwitzerland.

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