Exome-wide association study in 54,698 south Asians identifies novel type 2 diabetes associations with RNF19A, HNF4A, and dissects role of coding variants in GP2 and CDKAL1 Article Swipe
Sam Hodgson
,
Van-Minh Bui
,
Margherita Bigossi
,
Daniel Stow
,
Cyrielle Maroteau
,
Alice Williamson
,
Siqi Hu
,
Alexandra M. Blee
,
Adem Y. Dawed
,
Julia Carrasco-Zanini
,
Viswanathan Baskar
,
Saravanan Jebarani
,
Benjamin Meir Jacobs
,
Georgios Kalantzis
,
Stuart Rison
,
Klaudia Walter
,
Erwan Pennarun
,
Hilary C. Martin
,
Inês Barroso
,
Venkatesan Radha
,
Rajendra Pradeepa
,
Claudia Langenberg
,
Viswanathan Mohan
,
Anjana Ranjit Mohan
,
David A. van Heel
,
Amit R. Majithia
,
Yalda Jamshidi
,
Sarah Finer
,
Moneeza K. Siddiqui
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.09.24.25336527
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.09.24.25336527
Type 2 diabetes (T2D) disproportionately affects individuals of South Asian ancestry, yet the underlying genetic aetiology remains poorly understood and in genetic studies these populations remain underrepresented. We conducted an exome-wide association study (ExWAS) in 13,674 T2D cases and 41,024 controls of British-Bangladeshi and -Pakistani ancestry from the Genes & Health study, focusing on damaging coding variants in single-variant and gene-level analyses. This represents the largest ExWAS of T2D to date. We tested the association of novel genes and variants with metabolic traits in Genes & Health, UK, Madras Diabetes Research Foundation Biobank, India (MDRF), and the UK Biobank. Gene-level analyses revealed novel associations with RNF19A (p = 1.8×10⁻¹□) and HNF4A (p = 2.4×10⁻¹³), a known monogenic diabetes gene. The HNF4A signal was driven by a South Asian-specific gain-of-function variant (rs150776703, Pro437Ser) protective against T2D (OR = 0.48, p = 2.8×10⁻ ¹□), diabetic eye disease, and gestational diabetes but associated with elevated LDL-cholesterol, plasma PCSK9 upregulation, and increased myocardial infarction risk (HR = 1.62, p = 0.01). In Huh7 cells, Pro437Ser demonstrated similar transactivation of HNF4A target, G6PC , compared to wild-type, partially explaining the protective effect for T2D. Single-variant analyses highlighted a missense variant in CDKAL1 and a T2D risk-increasing South Asian-specific variant, rs78193826 ( GP2 : Val429Met), linked to CKD risk and beta-cell dysfunction (via stimulated C-peptides). Meta-analysis with UK Biobank highlights a role for plasma GP2 levels as a biomarker for high genetic risk of beta-cell deficiency and low risk for obesity-mediated T2D. These novel findings provide a foundation for drug target development, precision medicine and deeper exploration of metabolic and cardiovascular disease mechanisms in global populations disproportionately affected by T2D.
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- article
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.09.24.25336527
- OA Status
- green
- References
- 50
- OpenAlex ID
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- Title
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Exome-wide association study in 54,698 south Asians identifies novel type 2 diabetes associations with RNF19A, HNF4A, and dissects role of coding variants in GP2 and CDKAL1Work title
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articleOpenAlex work type
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enPrimary language
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2025Year of publication
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2025-09-26Full publication date if available
- Authors
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Sam Hodgson, Van-Minh Bui, Margherita Bigossi, Daniel Stow, Cyrielle Maroteau, Alice Williamson, Siqi Hu, Alexandra M. Blee, Adem Y. Dawed, Julia Carrasco-Zanini, Viswanathan Baskar, Saravanan Jebarani, Benjamin Meir Jacobs, Georgios Kalantzis, Stuart Rison, Klaudia Walter, Erwan Pennarun, Hilary C. Martin, Inês Barroso, Venkatesan Radha, Rajendra Pradeepa, Claudia Langenberg, Viswanathan Mohan, Anjana Ranjit Mohan, David A. van Heel, Amit R. Majithia, Yalda Jamshidi, Sarah Finer, Moneeza K. SiddiquiList of authors in order
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https://doi.org/10.1101/2025.09.24.25336527Publisher landing page
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https://doi.org/10.1101/2025.09.24.25336527Direct OA link when available
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| abstract_inverted_index.(via | 217 |
| abstract_inverted_index.G6PC | 178 |
| abstract_inverted_index.Huh7 | 169 |
| abstract_inverted_index.T2D. | 189, 246, 274 |
| abstract_inverted_index.This | 63 |
| abstract_inverted_index.Type | 1 |
| abstract_inverted_index.drug | 254 |
| abstract_inverted_index.from | 47 |
| abstract_inverted_index.high | 235 |
| abstract_inverted_index.risk | 161, 213, 237, 243 |
| abstract_inverted_index.role | 226 |
| abstract_inverted_index.with | 81, 105, 151, 221 |
| abstract_inverted_index.& | 50, 86 |
| abstract_inverted_index.(T2D) | 4 |
| abstract_inverted_index.0.48, | 138 |
| abstract_inverted_index.1.62, | 164 |
| abstract_inverted_index.Asian | 10 |
| abstract_inverted_index.ExWAS | 67 |
| abstract_inverted_index.Genes | 49, 85 |
| abstract_inverted_index.HNF4A | 111, 121, 176 |
| abstract_inverted_index.India | 94 |
| abstract_inverted_index.PCSK9 | 155 |
| abstract_inverted_index.South | 9, 127, 202 |
| abstract_inverted_index.These | 247 |
| abstract_inverted_index.cases | 38 |
| abstract_inverted_index.date. | 71 |
| abstract_inverted_index.gene. | 119 |
| abstract_inverted_index.genes | 78 |
| abstract_inverted_index.known | 116 |
| abstract_inverted_index.novel | 77, 103, 248 |
| abstract_inverted_index.study | 33 |
| abstract_inverted_index.these | 24 |
| abstract_inverted_index.0.01). | 167 |
| abstract_inverted_index.13,674 | 36 |
| abstract_inverted_index.41,024 | 40 |
| abstract_inverted_index.CDKAL1 | 197 |
| abstract_inverted_index.Health | 51 |
| abstract_inverted_index.Madras | 89 |
| abstract_inverted_index.RNF19A | 106 |
| abstract_inverted_index.cells, | 170 |
| abstract_inverted_index.coding | 56 |
| abstract_inverted_index.deeper | 260 |
| abstract_inverted_index.driven | 124 |
| abstract_inverted_index.effect | 187 |
| abstract_inverted_index.global | 269 |
| abstract_inverted_index.levels | 230 |
| abstract_inverted_index.linked | 210 |
| abstract_inverted_index.plasma | 154, 228 |
| abstract_inverted_index.poorly | 18 |
| abstract_inverted_index.remain | 26 |
| abstract_inverted_index.signal | 122 |
| abstract_inverted_index.study, | 52 |
| abstract_inverted_index.target | 255 |
| abstract_inverted_index.tested | 73 |
| abstract_inverted_index.traits | 83 |
| abstract_inverted_index.(ExWAS) | 34 |
| abstract_inverted_index.(MDRF), | 95 |
| abstract_inverted_index.Biobank | 223 |
| abstract_inverted_index.Health, | 87 |
| abstract_inverted_index.affects | 6 |
| abstract_inverted_index.against | 134 |
| abstract_inverted_index.disease | 266 |
| abstract_inverted_index.genetic | 15, 22, 236 |
| abstract_inverted_index.largest | 66 |
| abstract_inverted_index.provide | 250 |
| abstract_inverted_index.remains | 17 |
| abstract_inverted_index.similar | 173 |
| abstract_inverted_index.studies | 23 |
| abstract_inverted_index.target, | 177 |
| abstract_inverted_index.variant | 130, 195 |
| abstract_inverted_index.¹□), | 142 |
| abstract_inverted_index.Abstract | 0 |
| abstract_inverted_index.Biobank, | 93 |
| abstract_inverted_index.Biobank. | 99 |
| abstract_inverted_index.Diabetes | 90 |
| abstract_inverted_index.Research | 91 |
| abstract_inverted_index.affected | 272 |
| abstract_inverted_index.analyses | 101, 191 |
| abstract_inverted_index.ancestry | 46 |
| abstract_inverted_index.compared | 180 |
| abstract_inverted_index.controls | 41 |
| abstract_inverted_index.damaging | 55 |
| abstract_inverted_index.diabetes | 3, 118, 148 |
| abstract_inverted_index.diabetic | 143 |
| abstract_inverted_index.disease, | 145 |
| abstract_inverted_index.elevated | 152 |
| abstract_inverted_index.findings | 249 |
| abstract_inverted_index.focusing | 53 |
| abstract_inverted_index.medicine | 258 |
| abstract_inverted_index.missense | 194 |
| abstract_inverted_index.revealed | 102 |
| abstract_inverted_index.variant, | 204 |
| abstract_inverted_index.variants | 57, 80 |
| abstract_inverted_index.Pro437Ser | 171 |
| abstract_inverted_index.aetiology | 16 |
| abstract_inverted_index.analyses. | 62 |
| abstract_inverted_index.ancestry, | 11 |
| abstract_inverted_index.beta-cell | 215, 239 |
| abstract_inverted_index.biomarker | 233 |
| abstract_inverted_index.conducted | 29 |
| abstract_inverted_index.increased | 158 |
| abstract_inverted_index.metabolic | 82, 263 |
| abstract_inverted_index.monogenic | 117 |
| abstract_inverted_index.partially | 183 |
| abstract_inverted_index.precision | 257 |
| abstract_inverted_index.-Pakistani | 45 |
| abstract_inverted_index.2.8×10⁻ | 141 |
| abstract_inverted_index.Foundation | 92 |
| abstract_inverted_index.Gene-level | 100 |
| abstract_inverted_index.Pro437Ser) | 132 |
| abstract_inverted_index.associated | 150 |
| abstract_inverted_index.deficiency | 240 |
| abstract_inverted_index.exome-wide | 31 |
| abstract_inverted_index.explaining | 184 |
| abstract_inverted_index.foundation | 252 |
| abstract_inverted_index.gene-level | 61 |
| abstract_inverted_index.highlights | 224 |
| abstract_inverted_index.infarction | 160 |
| abstract_inverted_index.mechanisms | 267 |
| abstract_inverted_index.myocardial | 159 |
| abstract_inverted_index.protective | 133, 186 |
| abstract_inverted_index.represents | 64 |
| abstract_inverted_index.rs78193826 | 205 |
| abstract_inverted_index.stimulated | 218 |
| abstract_inverted_index.underlying | 14 |
| abstract_inverted_index.understood | 19 |
| abstract_inverted_index.wild-type, | 182 |
| abstract_inverted_index.Val429Met), | 209 |
| abstract_inverted_index.association | 32, 75 |
| abstract_inverted_index.dysfunction | 216 |
| abstract_inverted_index.exploration | 261 |
| abstract_inverted_index.gestational | 147 |
| abstract_inverted_index.highlighted | 192 |
| abstract_inverted_index.individuals | 7 |
| abstract_inverted_index.populations | 25, 270 |
| abstract_inverted_index.C-peptides). | 219 |
| abstract_inverted_index.associations | 104 |
| abstract_inverted_index.demonstrated | 172 |
| abstract_inverted_index.development, | 256 |
| abstract_inverted_index.(rs150776703, | 131 |
| abstract_inverted_index.Meta-analysis | 220 |
| abstract_inverted_index.upregulation, | 156 |
| abstract_inverted_index.Asian-specific | 128, 203 |
| abstract_inverted_index.Single-variant | 190 |
| abstract_inverted_index.cardiovascular | 265 |
| abstract_inverted_index.single-variant | 59 |
| abstract_inverted_index.risk-increasing | 201 |
| abstract_inverted_index.transactivation | 174 |
| abstract_inverted_index.1.8×10⁻¹□) | 109 |
| abstract_inverted_index.2.4×10⁻¹³), | 114 |
| abstract_inverted_index.LDL-cholesterol, | 153 |
| abstract_inverted_index.gain-of-function | 129 |
| abstract_inverted_index.obesity-mediated | 245 |
| abstract_inverted_index.underrepresented. | 27 |
| abstract_inverted_index.disproportionately | 5, 271 |
| abstract_inverted_index.British-Bangladeshi | 43 |
| cited_by_percentile_year | |
| corresponding_author_ids | https://openalex.org/A5037452923 |
| countries_distinct_count | 5 |
| institutions_distinct_count | 29 |
| corresponding_institution_ids | https://openalex.org/I166337079 |
| citation_normalized_percentile.value | 0.43965538 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |