2009 Vienna - European Society of Human Genetics

Concurrent Sessions
University of Washington, Seattle, WA, United States, 8 Department of Twin
research & Genetic Epidemiology, King’s College, London, United Kingdom,
9 Institute of Biomedical and Clinical Science, Peninsula Medical School, Exter,
United Kingdom, 10 Department of Medicine, University of Maryland School of
Medicine, Baltimore, MD, United States, 11 Department of Biostatistics University
of Washington, Seattle, WA, United States, 12 Human Genetics Center, University
of Texas Health Science Center, Houston, TX, United States, 13 Longitudinal
Studies Section, Clinical Research Branch, Gerontology Research Center,
National Institute on Aging, Baltimore, MD, United States, 14 University of Iceland,
Reykjavik, Iceland, 15 Hebrew Senior-Life Institute for Aging Research and
Harvard Medical School, Boston, MA, United States, 16 Department of Epidemiology,
University of Washington, Seattle, WA, United States, 17 Laboratory
of Epidemiology, Demography, and Biometry, Intramural Research Program,
National Institute on Aging, Bethesda, MD, United States, 18 Division of Epidemiology
and Community Health, School of Public Health, University of Minnesota,
Minneapolis, MN, United States, 19 Department of Biostatistics, Boston University
School of Public Health, Boston, MA, United States.
Menopause, defined by the cessation of the menstrual cycle due to
depletion of the follicle pool, influences a woman’s well-being and is an
important risk factor for several major age-related diseases including
cardiovascular diseases, osteoarthritis and osteoporosis. The heritability
of age at natural menopause is estimated to be ~60%, suggesting a
strong genetic component. While few candidate gene polymorphisms
are associated with age at menopause, the genetic risk factors are
largely unknown.
We conducted a meta-analysis of genome-wide association studies
with >2,500,000 SNPs for age at natural menopause in 10,399 postmenopausal
Caucasian women from 9 population-based cohorts.
We identified 20 SNPs on chromosome 19q13.4 and chromosome
20p12.3 that reached genome-wide significance (p-value < 5*10-8).
The chromosome 19 SNPs are located on the same locus in BRSK1
and LOC284417, the most significant SNP is associated with 0.47
year earlier menopause per allele copy (SE: 0.05, p-value 1.9*10-18).
BRSK1 is a brain-specific serine-threonine kinase, for which no link
with menopause could be established. The top hit on chromosome
20 is located in MCM8, and is associated with an 0.89 year earlier
menopause per copy of the minor allele (SE: 0.11, p-value: 2.2*10-15).
MCM8 is expressed in mouse ovaries and is involved in DNA replication.
No other loci reached genome-wide significance.
Our results provide evidence for common genetic variants regulating
the timing of ovarian aging although the precise mechanisms are unknown.
Additional studies are warranted to identify the causal variants
at these loci and to characterize their functional significance.
c10.4
Genome-wide association scan for bilirubin levels in a sardinian
population
S. Sanna 1 , F. Busonero 1 , A. Maschio 1 , P. F. McArdle 2 , G. Usala 1 , M. Dei 1 , S.
Lai 1 , A. Mulas 1 , M. Piras 1 , L. Perseu 1 , M. Masala 1 , M. Marongiu 1 , L. Crisponi 1 , S.
Naitza 1 , R. Galanello 3 , G. R. Abecasis 4 , A. R. Shuldiner 5,2 , D. Schlessinger 6 , A.
Cao 1 , M. Uda 1 ;
1 Istituto di Neurogenetica e Neurofarmacologia, CNR, Monserrato, Italy,
2 Division of Endocrinology, Diabetes and Nutrition, University of Maryland
School of Medicine, Baltimore, MD, United States, 3 Clinica Pediatrica, Ospedale
Regionale delle Microcitemie, Dipartimento di Scienze Biomediche e
Biotecnologie,Università degli Studi di Cagliari, Cagliari, Italy, 4 Center for Statistical
Genetics, Department of Biostatistics, University of Michigan, Ann Arbor,
MI, United States, 5 Geriatric Research and Education Clinical Center, Veterans
Administration Medical Center, Baltimore, MD, United States, 6 Laboratory of
Genetics, National Institute on Aging, Baltimore, MD, United States.
Bilirubin is the final product of heme degradation. Unconjugated bilirubin
is transported into hepatocytes, where it is glucuronidated by
UGT1A1 and secreted into the bile canaliculi in its conjugated form.
Recent studies have shown that elevated bilirubin levels in adults are
inversely associated with the risk of developing coronary artery disease
and directly with gallstones, while unconjugated hyperbilirubinemia
may be associated with susceptibility to drug toxicity. The genetic factors
so far identified cannot fully explain the trait heritability, estimated
to be around 45%. To identify additional loci, we conducted a genomewide
association scan (GWAS) in 4300 Sardinians from the SardiNIA
project, genotyped using the Affymetrix 500K and 10K Arrays, and
evaluated the additive effect of 362,129 SNPs that passed quality control
tests. The GWAS results revealed, in addition to two known loci,
UGT1A1 (p=6.2x10 -62 ) and G6PD (p=2.5x10 -8 ), a strong association on
chromosome 12p12.2 (p=3.9x10 -9 ). The findings were replicated in an
independent sample of 1860 Sardinians and in 832 Amish individuals
from the HAPI Heart Study (overall pvalue