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HLA and genomewide allele sharing in dizygotic twins.

ABSTRACT: Gametic selection during fertilization or the effects of specific genotypes on the viability of embryos may cause a skewed transmission of chromosomes to surviving offspring. A recent analysis of transmission distortion in humans reported significant excess sharing among full siblings. Dizygotic (DZ) twin pairs are a special case of the simultaneous survival of two genotypes, and there have been reports of DZ pairs with excess allele sharing around the HLA locus, a candidate locus for embryo survival. We performed an allele-sharing study of 1,592 DZ twin pairs from two independent Australian cohorts, of which 1,561 pairs were informative for linkage on chromosome 6. We also analyzed allele sharing in 336 DZ twin pairs from The Netherlands. We found no evidence of excess allele sharing, either at the HLA locus or in the rest of the genome. In contrast, we found evidence of a small but significant (P=.003 for the Australian sample) genomewide deficit in the proportion of two alleles shared identical by descent among DZ twin pairs. We reconciled conflicting evidence in the literature for excess genomewide allele sharing by performing a simulation study that shows how undetected genotyping errors can lead to an apparent deficit or excess of allele sharing among sibling pairs, dependent on whether parental genotypes are known. Our results imply that gene-mapping studies based on affected sibling pairs that include DZ pairs will not suffer from false-positive results due to loci involved in embryo survival.

SUBMITTER: Montgomery GW

PROVIDER: S-EPMC1698703 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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HLA and genomewide allele sharing in dizygotic twins.

Montgomery Grant W GW Zhu Gu G Hottenga Jouke Jan JJ Duffy David L DL Heath Andrew C AC Boomsma Dorret I DI Martin Nicholas G NG Visscher Peter M PM

American journal of human genetics 20061023 6

Gametic selection during fertilization or the effects of specific genotypes on the viability of embryos may cause a skewed transmission of chromosomes to surviving offspring. A recent analysis of transmission distortion in humans reported significant excess sharing among full siblings. Dizygotic (DZ) twin pairs are a special case of the simultaneous survival of two genotypes, and there have been reports of DZ pairs with excess allele sharing around the HLA locus, a candidate locus for embryo sur ...[more]

PMID: 17186463

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Project description:ImportanceLow birth weight is associated with an increased likelihood of neurodivergence and neurodevelopmental conditions (NDCs) such as autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. However, it is unclear whether birth weight contributes independently to NDCs or whether the association is predominantly driven by genetic predisposition.ObjectiveTo estimate the associations between birth weight and dimensional (trait) and categorical (diagnoses) NDC outcomes, while adjusting for genetic risks.Design, setting, and participantsA co-twin design was applied to this case-control study conducted in Sweden. Diagnostic assessments were conducted between August 2011 and March 2022, within the Roots of Autism and ADHD Twin Study in Sweden (RATSS) during a 2.5-day participant visit to the clinic. The RATSS sample comprised phenotyped monozygotic and dizygotic twins enriched for NDCs. Data analysis was conducted in November 2022.ExposureBirth weight.Main outcomes and measuresCategorical and dimensional operationalizations of autism, ADHD, and intellectual disability were assessed. Generalized estimating equation models were fitted across and within twin pairs.ResultsThe study sample included 393 twins: 230 were monozygotic and 159 were dizygotic (zygosity was unknown for 4). Their median age was 15 (range, 8-37) years. There were 185 female participants (47.1%) and 208 male participants (52.9%). Across twin pairs, higher birth weight was associated with fewer autistic traits (unstandardized β [B], -5.51 [95% CI, -10.09 to -0.94]) and lower odds of autism diagnosis (OR, 0.63 [95% CI, 0.45 to 0.88]) and intellectual disability (OR, 0.42 [95% CI, 0.19 to 0.92]). Within pairs, the association between birth weight and dimensional autism (B, -17.35 [95% CI, -28.66 to -6.04]) and categorical autism (OR, 0.02 [95% CI, 0.001 to 0.42]) remained among monozygotic pairs but not dizygotic pairs. In addition, higher birth weight was associated with lower odds of ADHD diagnosis (OR, 0.003 [95% CI, 0 to 0.70]), fewer ADHD traits (B, -0.25 [95% CI, -0.39 to -0.11]), and higher IQ ratings (B, 7.43 [95% CI, 1.05 to 13.82]) among monozygotic twins.Conclusions and relevanceThe findings of this co-twin study suggest an association between low birth weight and NDCs, but they also acknowledge the importance of genetics because the associations observed were only statically significant among monozygotic twins. It is of pivotal importance to facilitate early identification of factors contributing to fetal growth restriction to minimize detrimental outcomes.

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HLA and genomewide allele sharing in dizygotic twins.

Publications

HLA and genomewide allele sharing in dizygotic twins.

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