PDF《and asthma》

OPEN ORIGINAL ARTICLE Identifying rare variants for genetic risk through a combined pedigree and phenotype approach: application to suicide and asthma TM Darlington1 , R Pimentel2 , K Smith2,3 , AV Bakian1 , L Jerominski1 , J Cardon1 , NJ Camp4 , WB Callor5 , T Grey5 , M Singleton6 , M Yandell6 , PF Renshaw1,7 , DA Yurgelun-Todd1,7 , D Gray1 and H Coon1 Suicidal behavior is a complex disorder, with evidence for genetic risk independent of other genetic risk factors including psychiatric disorders.

Since 1996, over

3000 DNA samples from Utah suicide decedents have been collected and banked for research use through the Utah Medical Examiner. In addition, over

12 000 Utah suicides were identi?ed through examination of death certi?cates back to 1904. By linking this data with the Utah Population Database, we have identi?ed multiple extended pedigrees with increased risk for suicide completion. A number of medical conditions co-occur with suicide, including asthma, and this study was undertaken to identify genetic risk common to asthma and suicide. This study tests the hypothesis that a particular comorbid condition may identify a more homogeneous genetic subgroup, facilitating the identi?cation of speci?c genetic risk factors in that group. From pedigrees at increased risk for suicide, we identi?ed three pedigrees also at signi?cantly increased familial risk for asthma. Five suicide decedents from each of these pedigrees, plus an additional three decedents not from these pedigrees with diagnosed asthma, and

10 decedents with close relatives with asthma were genotyped. Results were compared with

183 publicly available unaffected control exomes from

1000 Genomes and CEPH (Centre d'

etude du polymorphisme humain) samples genotyped on the same platform. A further

432 suicide decedents were also genotyped as non-asthma suicide controls. Genotyping was done using the In?nium HumanExome BeadChip. For analysis, we used the pedigree extension of Variant Annotation, Analysis and Search Tool (pVAAST) to calculate the disease burden of each gene. The Phenotype Driven Variant Ontological Re-ranking tool (Phevor) then re-ranked our pVAAST results in context of the phenotype. Using asthma as a seed phenotype, Phevor traversed biomedical ontologies and identi?ed genes with similar biological properties to those known to result in asthma. Our top associated genes included those related to neurodevelopment or neural signaling (brain-derived neurotrophic factor (BDNF), neutral sphingomyelinase

2 (SMPD2), homeobox b2 (HOXB2), neural cell adhesion molecule (NCAM2), heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0)), in?ammation (free fatty acid receptor

2 (FFAR2)) and in?ammation with additional evidence of neuronal involvement (oxidized low density lipoprotein receptor

1 (OLR1), toll-like receptor

3 (TLR3)). Of particular interest, BDNF has been previously implicated in both psychiatric disorders and asthma. Our results demonstrate the utility of combining pedigree and co-occurring phenotypes to identify rare variants associated with suicide risk in conjunction with speci?c co-occurring conditions. Translational Psychiatry (2014) 4, e471;

doi:10.1038/tp.2014.111;

published online

21 October

2014 INTRODUCTION In the United States, suicide is consistently in the top

10 leading causes of death, with over 38,000 reported in 2010.1 The Rocky Mountain states, in particular Utah, have elevated rates of completed suicide compared with the United States as a whole, with 17.5 and 11.8 suicides per

100 000, respectively, in 2009.2 Not only is the increased societal burden in Utah a compelling reason to conduct suicide research, but there are resources available to University of Utah researchers which make this an ideal setting. The Utah State Of?ce of the Medical Examiner (OME) is centralized for the entire state and located on the University of Utah campus, which provides broad ascertainment, consistency in determining cause of death, and consistency in tissue/?uid collection for genetic and toxicology data. Information on suicide decedents from the OME is currently linked to pedigree, demographic and medical data available from the Utah Population Database (UPDB), an invaluable epidemiological resource with demographic, familial and medical data on 7.3 million individuals.3 This linking allows for identi?cation of high-risk pedigrees, as well as characterization of psychiatric and physiological comorbidities. In conjunction with these resources, our laboratory recently reported the identi?cation of several Utah pedigrees with increased risk for completed suicide.4 Several hypotheses have been proposed that attempt to explain the increased rates of suicide in Utah, speci?cally highlighting air quality and elevation.5 Utah, especially its large population