was insufficient to adequately detect linkage and they lacked definite criteria for what constituted as homosexuality (the researchers depended on their own judgement and sometimes based their judgement on a single question to the subject). They also lacked criteria "to select appropriate families for the study of a putative X-linked locus" — as they did not select families based on the presence of maternal transmission of homosexuality, the Xq28 contribution to male sexual orientation may have been hidden. In addition, the meta-analysis revealed that the family pedigree data of Rice et al. (1999), in contrast to the genotyping data, seemed to support X chromosome linkage for homosexuality. In 2012, a large, comprehensive genome-wide linkage study of male sexual orientation was conducted by several independent groups of researchers. The study population included 409 independent pairs of gay brothers from 384 families, who were analyzed with over 300,000 single-nucleotide polymorphism markers. The study confirmed the Xq28 linkage to homosexuality by two-point and multipoint (MERLIN) LOD score mapping. Significant linkage was also detected in the region near the centromere of chromosome 8, overlapping with one of the regions detected in a previous genomewide linkage study by the Hamer lab. The authors concluded that "our findings, taken in context with previous work, suggest that genetic variation in each of these regions contributes to development of the important psychological trait of male sexual orientation." It was the largest study of the genetic basis of homosexuality to date and was published online in November 2014. In August 2019, a genome-wide association study of 493,001 individuals concluded that hundreds or thousands of genetic variants underlie homosexual behavior in both sexes, with 5 variants in particular being significantly associated. They stated that in contrast to linkage studies that found substantial association of sexual orientation with variants on the X-chromosome, they found no excess of signal (and no individual genome-wide significant variants) on Xq28 or the rest of the X chromosome. Other contents Xq28 is a large, complex, and gene-dense region. Among its various genes are the 12 genes of the melanoma-associated antigen (MAGE) family, of which MAGEA11 has been identified as a coregulator for the androgen receptor. Mutations involving the production of extra copies of the MECP2 and IRAK1 genes within Xq28 have been associated with phenotypes including anxiety and autism in mice. See also Biology and sexual orientation Daily Mail#Gay gene controversy The Science of Desire Notes