CORRESPONDENCE
A genome-wide scan of male sexual orientation
Journal of Human Genetics (2010) 55, 131–132; doi:10.1038/jhg.2009.135; published online 8 January 2010
Genetic-epidemiological studies provide
some evidence for a genetic component to
male homosexuality.1 Mustanski et al.2
performed the first genome-wide linkage
scan for male homosexuality using 403
microsatellite markers. The highest multipoint
logarithm of the odds (LOD) score
found by Mustanski et al.2 was 3.45 near
the microsatellite D7S798 on chromosome
7q36 with approximately equivalent maternal
and paternal contributions. As with all studies
of complex traits, this result requires confirmation.
Single-nucleotide polymorphism (SNP)-
based scans for linkage provide significantly
greater genomic coverage and information
content than do microsatellite assays;3
hence, we applied this technology to study a
Canadian cohort of homosexual males.
A total of 55 Canadian Caucasian families
with two or more homosexual male siblings
were studied, ascertained as previously
described.4 DNA samples were normalized
for concentration before labeling and hybridization
to the Illumina HumanLinkage-12
BeadChip Infinium array (Illumina, San Diego,
CA, USA), which comprises B6000 welldefined
SNPs spread comparatively evenly
across the human genome. The markers on
the array exhibit low levels of linkage disequilibrium,
and are thus suited for initial
genome-wide screens. Genotype calls, generated
using BeadStudio (Illumina), were
obtained for 112 individuals. Pedigrees were
verified using Pedstats,5 and data sets checked
for unlikely genotypes; suspect sample SNP data
points were removed from subsequent
analyses. Nonparametric linkage analyses
were carried out using MERLIN (http://
www.sph.umich.edu/csg/abecasis/Merlin/index.html).6
The results of the genome-wide linkage
scan are shown in Figure 1.
A LOD score peak of 2.86 was obtained on
chromosome 14 for SNP rs760335 (98.8cM,
position 93 884 697; genome build 36). The
adjacent SNP loci are rs733559 (96.8 cM;
92 809 308, LOD¼2.08) and rs742893 (99.7
cM; 94 222 866, LOD¼1.74). Modeling of
marker–marker linkage disequilibrium in
the data set (r240.1) did not significantly
alter the magnitude of LOD scores obtained
(rs760335, maximum LOD¼2.47). However,
when we analyzed 1000 simulated data sets of
pedigree genotypes generated by MERLIN, a
LOD score of X2.47 was obtained in 256 of
the 1000 simulations, generating an empirical
Non−parametric linkage analysis
H samples, pairs data
Chromosome
LOD score
−3
−2
−1
0
1
2
3
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 22 X XY
Figure 1 Genome-wide LOD scores for linkage across all chromosomes.
Journal of Human Genetics (2010) 55, 131–132
& 2010 The Japan Society of Human Genetics All rights reserved 1434-5161/10 $32.00
www.nature.com/jhgP-value for our linkage peak of 0.256. There
was no evidence for linkage at or around
7q32 (LOD¼0.2).
Therefore, in summary, although we could
find no evidence for linkage at 7q32 as found
by Mustanski et al.2 and as the LOD scores we
obtained failed to reach genome-wide significance
as defined by Lander and Kruglyak,7 the
studies combined provide information regarding
the magnitude of effects likely to be attributable
to male homosexuality genes if they do
indeed exist. Differences in the two studies may
lie in genetic and population heterogeneity, but
it is more probable that genes involved in male
homosexuality exert more modest effects than
detectable by linkage.8 More powerful genetic
studies will be required to find any relevant
genes. Parent-of-origin effects in male homosexuality
have been documented,2 and thus
consideration of epigenetic mechanisms are
also strongly warranted.9
Sreeram V Ramagopalan1,2, David
A Dyment1,2, Lahiru Handunnetthi1,2,
George P Rice3 and George C Ebers1,2
1Wellcome Trust Centre for Human
Genetics, University of Oxford, Oxford,
UK; 2Department of Clinical Neurology,
The John Radcliffe Hospital, University
of Oxford, Oxford, UK and 3Department of
Clinical Neurological Sciences, University of
Western Ontario, London, Ontario, Canada
E-mail:
george.ebers@clneuro.ox.ac.uk1 Bailey, J. M., Pillard, R. C., Dawood, K., Miller, M. B.,
Farrer, L. A., Trivedi, S. et al. A family history study
of male sexual orientation using three independent
samples. Behav. Genet. 29, 79–86 (1999).
2 Mustanski, B. S., Dupree, M. G., Nievergelt, C. M.,
Bocklandt, S., Schork, N. J. & Hamer, D. H. A genomewide
scan of male sexual orientation. Hum. Genet. 116,
272–278 (2005).
3 Middleton, F. A., Pato, M. T., Gentile, K. L., Morley, C.
P., Zhao, X., Eisener, A. F. et al. Genomewide linkage
analysis of bipolar disorder by use of a high-density
single-nucleotide-polymorphism (SNP) genotyping
assay: a comparison with microsatellite marker assays
and finding of significant linkage to chromosome 6q22.
Am. J. Hum. Genet. 74, 886–897 (2004).
4 Rice, G., Anderson, C., Risch, N. & Ebers, G. Male
homosexuality: absence of linkage to microsatellite
markers at Xq28. Science 284, 665–667 (1999).
5 Wigginton, J. E. & Abecasis, G. R. PEDSTATS: descriptive
statistics, graphics and quality assessment for gene
mapping data. Bioinformatics 21, 3445–3447 (2005).
6 Abecasis, G. R., Cherny, S. S., Cookson, W. O. &
Cardon, L. R. Merlin—rapid analysis of dense genetic
maps using sparse gene flow trees. Nat. Genet. 30,
97–101 (2002).
7 Lander, E. & Kruglyak, L. Genetic dissection of complex
traits: guidelines for interpreting and reporting linkage
results. Nat. Genet. 11, 241–247 (1995).
8 Risch, N. & Merikangas, K. The future of genetic
studies of complex human diseases. Science 273,
1516–1517 (1996).
9 Ramagopalan, S. V., Dyment, D. A. & Ebers, G. C.
Genetic epidemiology: the use of old and new tools
for multiple sclerosis. Trends Neurosci. 31, 645–652
(2008).
Correspondence
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