Regional autozygosity association with albumin-to-creatinine ratio reveals a novel FTO region in an Indigenous Australian population

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Abstract The genetic distinctiveness of Indigenous Australian populations is well established, yet the Tiwi population remains underrepresented in genetic research. Due to their prolonged geographic isolation, these populations are prone to increased runs of homozygosity (ROH). We investigated the genetic diversity of the Tiwi population, isolated from mainland Australia for decades, based on ROH and their associations with clinical traits. We analyzed 455 whole genome sequences to identify population structure via PCA and performed a comparison with UK Biobank, Melanesian, and Polynesian cohorts. ROH assessment and genome-wide and regional measures of homozygosity were used to explore associations between clinical traits and autozygosity. Our analysis revealed distinct genetic characteristics of the Tiwi population that aligned closely with those of the Melanesian cohort. Tiwi individuals exhibited an increased burden of ROH, particularly in LINC0109 , FMLN1 , and RPL17P45 genes on chromosomes 2, 17, and 18, respectively, indicating prolonged isolation and genetic drift. A positive correlation was observed between genomic F ROH and albumin-to-creatinine ratio (ACR) levels, suggesting a potential link between autozygosity and renal health markers. Furthermore, regional autozygosity association analysis revealed an association between elevated ACR and a region in FTO , implicating its role in obesity, kidney disease, and cardiovascular conditions. Importantly, we found that this association is strong under the recessive model. This research lays a robust foundation for further exploration of ROH mapping and its implications for disease susceptibility within Indigenous communities worldwide.

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