Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

Power, Robert A.; Nagoshi, Craig T.; DeFries, John C.; Plomin, Robert

doi:10.1038/ejhg.2013.155

Cited by 21 publications

(28 citation statements)

References 31 publications

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“…In particular, the estimate for Froh on general cognitive ability was more significant when SNP-by-SNP homozygosity, Fsnp , was removed as a covariate (β = −9.9, t(4852) = −2.92, p = 0.003), whereas Fsnp did not itself predict general cognitive ability (β = −0.1, t(4852) = −0.04, p = 0.97), and suggests that homozygosity at rare variants drove the observed Froh effect. Finally, contrary to a previous report (31), we found no evidence for increased assortative mating or inbreeding at the upper tail of the cognitive ability distribution.…”

Section: Resultscontrasting

confidence: 99%

“…To date, a number of studies have examined the effect of Froh burden and individual ROH regions on case/control and quantitative phenotypes, with early studies showing mixed results (30), including a non-significant Froh -cognitive ability relationship among individuals of European ancestry (N=2329) (31). Given the low variation in Froh among outbred samples, it is likely that these studies were underpowered (29).…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide autozygosity is associated with lower general cognitive ability

et al. 2015

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Inbreeding depression refers to lower fitness among offspring of genetic relatives (1). This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents (2). Using dense genome-wide SNP data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4,854 participants of European ancestry. We used runs of homozygosity—multiple homozygous SNPs in a row— to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 standard deviations among the offspring of first cousins (p = 0.003 - 0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome-wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships (3). These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

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Section: Resultscontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-wide autozygosity is associated with lower general cognitive ability

et al. 2015

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“…In the classical twin design, dominance variation (making dizygotic twins more dissimilar than half the similarity of monozygotic twins) can be obscured by shared environment effects (making dizygotic twins more similar). There is some evidence from other approaches that dominance only plays a minor role in intelligence differences [80][81][82][83].…”

Section: Discussionmentioning

confidence: 99%

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

et al. 2018

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Pedigree-based analyses of intelligence have reported that genetic differences account for 50-80% of the phenotypic variation. For personality traits these effects are smaller, with 34-48% of the variance being explained by genetic differences. However, molecular genetic studies using unrelated individuals typically report a heritability estimate of around 30% for intelligence and between 0 and 15% for personality variables. Pedigree-based estimates and molecular genetic estimates may differ because current genotyping platforms are poor at tagging causal variants, variants with low minor allele frequency, copy number variants, and structural variants. Using~20,000 individuals in the Generation Scotland family cohort genotyped for~700,000 single-nucleotide polymorphisms (SNPs), we exploit the high levels of linkage disequilibrium (LD) found in members of the same family to quantify the total effect of genetic variants that are not tagged in GWAS of unrelated individuals. In our models, genetic variants in low LD with genotyped SNPs explain over half of the genetic variance in intelligence, education, and neuroticism. By capturing these additional genetic effects our models closely approximate the heritability estimates from twin studies for intelligence and education, but not for neuroticism and extraversion. We then replicated our finding using imputed molecular genetic data from unrelated individuals to show that 50% of differences in intelligence, and~40% of the differences in education, can be explained by genetic effects when a larger number of rare SNPs are included. From an evolutionary genetic perspective, a substantial contribution of rare genetic variants to individual differences in intelligence, and education is consistent with mutation-selection balance.

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“…Studies on ROH and cognition in different strata of the general population have shown mixed results, with moderate effect sizes [6][7][8] . While two studies 6,8 suggest that inbreeding depression may decrease adult intelligence, divergent results by Power et al 7 could be explained in view of three evidences. First, assortative mating has recently been highlighted as an important factor underlying psychiatric and behavioral phenotypes [9][10][11][12] , in line with specific findings showing assortative mating in relation to cognitive ability published in the late 20 th century 13,14 genetic effects on brain structure and function, but the evidence of associations between genetic risk for schizophrenia and brain features is scarce, with some studies reporting no overlap between schizophrenia PGRS and subcortical phenotypes derived from magnetic resonance imaging (MRI) 21 ,…”

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confidence: 99%

Effects of autozygosity and schizophrenia polygenic risk on cognitive and brain developmental trajectories

Córdova‐Palomera

Kaufmann

Bettella

et al. 2017

Preprint

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Cognitive and brain development are determined by dynamic interactions between genes and environment across the lifespan. Aside from marker-by-marker analyses of polymorphisms, biologically meaningful features of the whole-genome (derived from the combined effect of individual markers) have been postulated to inform on human phenotypes including cognitive traits and their underlying biological substrate.Here, estimates of inbreeding and genetic susceptibility for schizophrenia calculated from genome-wide data -runs of homozygosity (ROH) and schizophrenia polygenic risk score (PGRS)-are analyzed in relation to cognitive abilities (n=4183) and brain structure (n=516) in a general-population sample of European-ancestry participants aged 8-22, from the Philadelphia Neurodevelopmental Cohort.The findings suggest that a higher ROH burden and higher schizophrenia PGRS are associated with higher intelligence. Cognition~ROH and cognition~PGRS associations obtained in this cohort may respectively evidence that assortative mating influences intelligence, and that individuals with high schizophrenia genetic risk who do not transition to disease status are cognitively resilient.Neuroanatomical data showed that the effects of schizophrenia PGRS on cognition could be modulated by brain structure, although larger imaging datasets are needed to accurately disentangle the underlying neural mechanisms linking IQ with both inbreeding and the genetic burden for schizophrenia.

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Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

Cited by 21 publications

References 31 publications

Genome-wide autozygosity is associated with lower general cognitive ability

Genome-wide autozygosity is associated with lower general cognitive ability

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

Effects of autozygosity and schizophrenia polygenic risk on cognitive and brain developmental trajectories

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