Quality Control of Genetic Samples

We identified poor quality samples using the metrics of missing rate and heterozygosity computed using a set of 605,876 high quality autosomal markers that were typed on both arrays (see Supplementary Information for criteria). Extreme values in one or both of these metrics can be indicators of poor sample quality due to, for example, DNA contamination^{15 (link)}. The heterozygosity of a sample—the fraction of non-missing markers that are called heterozygous—can also be sensitive to natural phenomena, including population structure, recent admixture and parental consanguinity. We took extra measures to avoid misclassifying good quality samples because of these effects. For example, we adjusted heterozygosity for population structure by fitting a linear regression model with the first six principal components in a PCA as predictors (Extended Data Fig. 1). Using this adjustment we identified 968 samples with unusually high heterozygosity or >5% missing rate (Supplementary Information). A list of these samples is provided as part of the data release.
We also conducted quality control specific to the sex chromosomes using a set of 15,766 high quality markers on the X and Y chromosomes. Affymetrix infers the sex of each individual based on the relative intensity of markers on the Y and X chromosomes¹⁶ . Sex is also reported by participants, and mismatches between these sources can be used as a way to detect sample mishandling or other kinds of clerical error. However, in a dataset of this size, some such mismatches would be expected due to transgender individuals, or instances of real (but rare) genetic variation, such as sex-chromosome aneuploidies^{17 (link)}. Affymetrix genotype calling on the X and Y chromosomes allows only haploid or diploid genotype calls, depending on the inferred sex¹⁶ . Therefore, cases of full or mosaic sex chromosome aneuploidies may result in compromised genotype calls on all, or parts of, the sex chromosomes (but not affect the autosomes). For example, individuals with karyotype XXY will probably have poorer quality genotype calls on the pseudo-autosomal region (PAR) of the X chromosome, as they are effectively triploid in this region. Using information in the measured intensities of chromosomes X and Y, we identified a set of 652 (0.134%) individuals with sex chromosome karyotypes putatively different from XY or XX (Fig. 2d, Supplementary Table 2). The list of samples is provided as part of the data release. Researchers wanting to identify sex mismatches should compare the self-reported sex and inferred sex data fields.
We did not remove samples from the data as a result of any of the above analyses, but rather provide the information as part of the data release. However, we excluded a small number of samples (835 in total) that we identified as sample duplicates (as opposed to identical twins, see Supplementary Information) or were probably involved in sample mishandling in the laboratory (~10), as well as participants who asked to be withdrawn from the project before the data release.