Influence of autozygosity on common disease risk across the phenotypic spectrum

Malawsky, Daniel S.; van Walree, Eva; Jacobs, Benjamin M.; Heng, Teng Hiang; Huang, Qin Qin; Sabir, Ataf H.; Rahman, Saadia; Sharif, Saghira Malik; Khan, Ahsan; Mirkov, Maša Umićević; Kuwahara, Hiroyuki; Gao, Xin; Alkuraya, Fowzan S.; Posthuma, Danielle; Newman, William G.; Griffiths, Christopher J.; Mathur, Rohini; van Heel, David A.; Finer, Sarah; O’Connell, Jared; Martin, Hilary C.

doi:10.1016/j.cell.2023.08.028

Cited by 9 publications

(5 citation statements)

References 69 publications

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“…Nevertheless, the plausibility of these more complex models with highly recessive strongly deleterious mutations are supported by previous theoretical and experimental work on dominance in non-human taxa [14,17,19,25,42] as well as the broad literature on recessive disease and inbreeding depression in humans [37, 40,41,[51][52][53][54][55][56]. Although we remain unable to determine an optimal dominance model in humans, our work provides a range of useful models that can be employed in future analyses [57].…”

Section: Discussionmentioning

confidence: 64%

“…To overcome this, we use a model averaging approach ( Table 1 ), which highlights some general trends, though does not necessarily indicate that complex models with recessive mutations are an improvement over an additive model. Nevertheless, the plausibility of these more complex models with highly recessive strongly deleterious mutations are supported by previous theoretical and experimental work on dominance in non-human taxa [14,17,19,25,42] as well as the broad literature on recessive disease and inbreeding depression in humans [37,40,41,51–56]. Although we remain unable to determine an optimal dominance model in humans, our work provides a range of useful models that can be employed in future analyses [57].…”

Section: Discussionmentioning

confidence: 90%

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Constraining models of dominance for nonsynonymous mutations in the human genome

Kyriazis,

Lohmueller

2024

Preprint

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Dominance is a fundamental parameter in genetics, determining the dynamics of natural selection on deleterious and beneficial mutations, the patterns of genetic variation in natural populations, and the severity of inbreeding depression in a population. Despite this importance, dominance parameters remain poorly known, particularly in humans or other non-model organisms. A key reason for this lack of information about dominance is that it is extremely challenging to disentangle the selection coefficient (s) of a mutation from its dominance coefficient (h). Here, we explore dominance and selection parameters in humans by fitting models to the site frequency spectrum (SFS) for nonsynonymous mutations. When assuming a single dominance coefficient for all nonsynonymous mutations, we find that numeroushvalues can fit the data, so long ashis greater than ∼0.15. Moreover, we also observe that theoretically-predicted models with a negative relationship betweenhandscan also fit the data well, including models withh=0.05 for strongly deleterious mutations. Finally, we use our estimated dominance and selection parameters to inform simulations revisiting the question of whether the out-of-Africa bottleneck has led to differences in genetic load between African and non-African human populations. These simulations suggest that the relative burden of genetic load in non-African populations depends on the dominance model assumed, with slight increases for more weakly recessive models and slight decreases shown for more strongly recessive models. Moreover, these results also demonstrate that models of partially recessive nonsynonymous mutations can explain the observed severity of inbreeding depression in humans, bridging the gap between molecular population genetics and direct measures of fitness in humans. Our work represents a comprehensive assessment of dominance and deleterious variation in humans, with implications for parameterizing models of deleterious variation in humans and other mammalian species.Author SummaryThe dominance coefficient (h) of a mutation determines its impact on organismal fitness when heterozygous. For instance, fully recessive mutations (h=0) have no effects on fitness when heterozygous whereas additive mutations (h=0.5) have an effect that is intermediate to the two heterozygous mutations. The extent to which deleterious mutations may be recessive, additive, or dominant is a key area of study in evolutionary genetics. However, dominance parameters remain poorly known in humans and most other organisms due to a variety of technical challenges. In this study, we aim to constrain the possible set of dominance and selection parameters for amino acid changing mutations in humans. We find that a wide range of models are possible, including models with a theoretically-predicted relationship betweenhands. We then use a range of plausible selection and dominance models to explore how deleterious variation may have been shaped by the out-of-Africa bottleneck in humans. Our results highlight the subtle influence of dominance on patterns of genetic load in humans and demonstrate that models of partially recessive mutations at amino-acid-changing sites can explain the observed effects of inbreeding on mortality in humans.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 90%

Constraining models of dominance for nonsynonymous mutations in the human genome

Kyriazis,

Lohmueller

2024

Preprint

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“…These results should be considered with care because of the potential socio-economic confounding factors of consanguinity ( Bittles and Black 2010 ). Attempts to correct for such confounding factors—by evaluating the consequences of different realized inbreeding levels between siblings or by assessing the influence of ROH in cohorts of different continental origins and with different homozygosity levels—confirmed the reported deleterious consequence of inbreeding ( The BioBank Japan Project et al 2015 ; Clark et al 2019 ; Malawsky et al 2023 ). Inbreeding depression is also found in natural populations of vertebrates (e.g.…”

Section: Discussionmentioning

confidence: 99%

Measuring the Efficiency of Purging by non-random Mating in Human Populations

Laurent,

Gineau,

Utge

et al. 2024

Molecular Biology and Evolution

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Human populations harbour a high concentration of deleterious genetic variants. Here, we tested the hypothesis that non-random mating practices affect the distribution of these variants, through exposure in the homozygous state, leading to their purging from the population gene pool. To do so, we produced whole-genome sequencing data for two pairs of Asian populations exhibiting different alliance rules and rates of inbreeding, but with similar effective population sizes. The results show that populations with higher rates of inbred matings do not purge deleterious variants more efficiently. Purging therefore has a low efficiency in human populations, and different mating practices lead to a similar mutational load.Keywords: purifying selection, kinship, mate choice, inbreeding, genomics, deleterious variants, mutational load

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“…Another round of variant filters was applied to include only autosomal, bi-alleleic SNPs with ≥99% call rate. The Pakistani subgroup has high autozygosity and strong population structure, while the Bangladeshi subgroup has minimal structure and much less autozygosity 18 , so to avoid excluding too many high-quality variants due to failure on a standard test for Hardy-Weinberg Equilibrium (HWE), the HWE test was performed (using PLINK1.9) 19 only in the Bangladeshi subgroup and the variants that failed a p-value threshold of 10 -6 in Bangladeshis were then excluded from the entire dataset. Variants with MAF>0.1% were included from the imputation backbone, which resulted in 469,678 variants that were then phased with EAGLE2 (Kpbwt=20,000) 20 .…”

Section: Methodsmentioning

confidence: 99%

“…A list of 237 custom phenotypes were compiled manually, and a second set of 1,281 phenotypes were defined based on International Classification of Disease (ICD10) codes. Further detail is described in Malawsky et al (2023) (Methods section on “Phenotypic data harmonisation and preparation for G&H”) 18 . We retained phenotypes with ≥30 cases and also classified them into those that affected both sexes or were sex-specific (i.e.…”

Section: Methodsmentioning

confidence: 99%

Widespread recessive effects on common diseases in a cohort of 44,000 British Pakistanis and Bangladeshis with high autozygosity

Heng,

Walter,

Huang

et al. 2024

Preprint

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Genetic association studies have focused on testing additive models in cohorts with European ancestry. Little is known about recessive effects on common diseases, specifically for non-European ancestry. Genes & Health is a cohort of British Pakistani and Bangladeshi individuals with elevated rates of consanguinity and endogamy, making it suitable to study recessive effects. We imputed variants into 44,190 genotyped individuals, using two imputation panels: a set of 4,982 whole-exome-sequences from within the cohort, and the TOPMed-r2 panel. We performed association testing with 898 diseases from electronic health records. We identified 185 independent loci that reached standard genome-wide significance (p<5x10-8) under the recessive model and had p-values more significant than under the additive model. 140 loci demonstrated nominally-significant (p<0.05) dominance deviation p-values, confirming a recessive association pattern. Sixteen loci in three clusters were significant at a Bonferroni threshold accounting for multiple phenotypes tested (p<5.5x10-12). In FinnGen, we replicated 44% of the expected number of Bonferroni-significant loci we were powered to replicate, at least one from each cluster, including an intronic variant in PNPLA3 (rs66812091) and non-alcoholic fatty liver disease, a previously reported additive association. We present novel evidence suggesting that the association is recessive instead (OR=1.3, recessive p=2x10-12, additive p=2x10-11, dominance deviation p=3x10-2, FinnGen recessive OR=1.3 and p=6x10-12). We identified a novel protective recessive association between a missense variant in SGLT4 (rs61746559), a sodium-glucose transporter with a possible role in the renin-angiotensin-aldosterone system, and hypertension (OR=0.2, p=3x10-8, dominance deviation p=7x10-6). These results motivate interrogating recessive effects on common diseases more widely.

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Influence of autozygosity on common disease risk across the phenotypic spectrum

Cited by 9 publications

References 69 publications

Constraining models of dominance for nonsynonymous mutations in the human genome

Constraining models of dominance for nonsynonymous mutations in the human genome

Measuring the Efficiency of Purging by non-random Mating in Human Populations

Widespread recessive effects on common diseases in a cohort of 44,000 British Pakistanis and Bangladeshis with high autozygosity

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