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S18: TESTIS 2
Moderators: Jorgen Thorup (Denmark), Anthony Caldamone (USA)
ESPU Meeting on Friday 16, October 2015, 15:34 - 16:16
15:34 - 15:37
S18-1
(PP)
PATHWAY ANALYSIS SUPPORTS ASSOCIATION OF NONSYNDROMIC
CRYPTORCHIDISM WITH GENETIC LOCI LINKED TO CYTOSKELETON-DEPENDENT
FUNCTIONS
Julia BARTHOLD
1
, Yanping WANG
2
, Thomas KOLON
3
, Claude KOLLIN
4
, Agneta NORDENSKJÖLD
4
, Alicia OLIVANT
FISHER
2
, T. Ernesto FIGUEROA
5
, Ahmad BANIHANI
5
, Jennifer HAGERTY
5
, Ricardo GONZALEZ
6
, Paul NOH
7
, Rosetta
CHIAVACCI
8
, Kisha HARDEN
8
, Debra ABRAMS
8
, Cecilia KIM
8
, Jin LI
8
, Hakon HAKONARSON
9
and Marcella DEVOTO
10
1) Nemours/Alfred I. duPont Hospital for Children, Research/Urology, Wilmington, USA - 2) Nemours/Alfred I. duPont
Hospital for Children, Research, Wilmington, USA - 3) The Children's Hospital of Philadelphia, Urology, Philadelphia, USA
- 4) Karolinska Institutet, Women's and Children's Health, Stockholm, SWEDEN - 5) Nemours/Alfred I. duPont Hospital
for Children, Division of Urology, Wilmington, USA - 6) Auf der Bult Kinder- und Jugendkrankenhaus, Hannover,
GERMANY - 7) Cincinnati Children's Hospital Medical Center, Division of Pediatric Urology, Cincinnati, USA - 8) The
Children's Hospital of Philadelphia, Center for Applied Genomics, Philadelphia, USA - 9) The Children's Hospital of
Philadelphia and Perelman School of Medicine, University of Pennsylvania, Center for Applied Genomics, Division of
Genetics, Department of Pediatrics, Philadelphia, USA - 10) The Children's Hospital of Philadelphia and Perelman School
of Medicine, University of Pennsylvania, Division of Genetics, Department of Pediatrics, and Department of Biostatistics
and Epidemiology, Philadelphia, USA
PURPOSE
As familial studies suggest moderate heritability of cryptorchidism, we designed the present studies to identify genomic
loci associated with the nonsyndromic form of the disease.
MATERIAL AND METHODS
We analyzed data from 844 cases and 2718 control males of European ancestry. Genotyping was performed using the
Illumina HumanHap550 and Human610-Quad (Group 1) or OmniExpress (Group 2) platform. We imputed genotypes
genome-wide, and combined single marker association results in meta-analyses for all cases and for secondary
subphenotype analyses based on testis position, laterality and age. Selected markers were genotyped in an
independent European case (n=306) and control (n=324) replication group. We used several bioinformatics tools to
analyze top (p≤10
-6
) and suggestive (p≤10
-4
) signals for enrichment of signaling pathways, cellular functions and
custom gene lists.
RESULTS
In the full analysis, we identified 21 top signals, none reaching genome-wide significance, but one passed this threshold
in a subgroup analysis of proximal testis position (rs55867206, near SH3PXD2B, OR=2.2 (95% CI 1.7, 2.9; p=2X10
-
9
). An additional 129 top loci emerged in at least one subphenotype analysis. Cytoskeleton-dependent molecular and
cellular functions were prevalent in pathway analysis of suggestive (p≤1X10
-4
) signals after multiple testing
correction. Cryptorchidism- and hypogonadism-associated genes, and gubernacular hormone-responsive and/or
differentially expressed genes were also significantly overrepresented. Markers in FMN1, encoding an actin-binding
protein, and near PAX3, involved in myogenesis, showed suggestive replication in the independent case-control
population.
CONCLUSIONS
These data suggest that cryptorchidism susceptibility is highly heterogeneous and/or not due to common variants, and
may overlap with the many known syndromic etiologies of the disease. Association with genes involved in cytoskeletal
pathways suggests a potential role for tissue specific effectors of androgen signaling.