Influence of autozygosity on common disease risk across the phenotypic spectrum

Malawsky, Daniel; Walree, Eva van; Jacobs, Benjamin Meir; Heng, Teng Hiang; Huang, Qin; Ataf, Sabir H; Rahman, Saadia; Sharif, Saghira Malik; Khan, Ahsan Ali; Mirkov, Maša Umićević; Posthuma, Daniëlle; Griffiths, Christopher J.; Mathur, Rohini; Heel, David A. van; Finer, Sarah; O’Connell, Jared; Martin, Hilary C.

doi:10.1101/2023.02.01.23285346

Cited by 2 publications

(2 citation statements)

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“…From another study within this cohort, Malawsky et al (2023) 75 demonstrated that increased homozygosity (higher F ROH ) was associated with multiple common diseases. The primary hypothesis for these associations is that 30 homozygous regions of the genome contained causal variants with recessive effects on these phenotypes 76 .…”

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confidence: 76%

“…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: Phenotype Curationmentioning

confidence: 99%

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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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confidence: 76%

Section: Phenotype Curationmentioning

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

Self Cite

View full text Add to dashboard Cite

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Mexican Biobank advances population and medical genomics of diverse ancestries

Sohail,

Palma-Martínez,

Chong

et al. 2023

Nature

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Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype–phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2–6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.

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Influence of autozygosity on common disease risk across the phenotypic spectrum

Cited by 2 publications

References 65 publications

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

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

Mexican Biobank advances population and medical genomics of diverse ancestries

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