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Hilary Martin @hilarycmartin.bsky.social · 7d

Pleased to have contributed to this paper out at @nature.com today from @vw1234.bsky.social and Yira (Xinhe) Zhang showing that the common variant contribution to autism varies substantially by age of diagnosis www.nature.com/articles/s41.... Critical for understanding heterogeneity in autism.

Polygenic and developmental profiles of autism differ by age at diagnosis - Nature

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

www.nature.com

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Hilary Martin @hilarycmartin.bsky.social · 24d

It was indeed a great conference, I really enjoyed it and would highly recommend to others! Excellent location too.

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Hilary Martin @hilarycmartin.bsky.social · Jul 25

Thanks to Chris Coates at Uni of Essex for writing this excellent blog about our work on common variants in neurodevelopment conditions www.nature.com/articles/s41..., using data from @genomicsengland.bsky.social , DDD, @usociety.bsky.social , ALSPAC and @clscohorts.bsky.social.

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Reposted by Hilary Martin

Emma Wade @emmaewade.bsky.social · Jul 3

Excited to share a new preprint from my time with @hilarycmartin.bsky.social's group 🥳 We found evidence both common and rare genetic variation contributed to early life mental health symptoms.

More info from co-first author @olivia-wootton.bsky.social ⬇️

Olivia Wootton @olivia-wootton.bsky.social · Jul 3

New preprint!🚨
"“The Contribution of Common and Rare Genetic Variation to Emotional and Behavioural Symptoms in Childhood and Adolescence” is out on medRxiv.
www.medrxiv.org/content/10.1...

Thread 👇

The Contribution of Common and Rare Genetic Variation to Emotional and Behavioural Symptoms in Childhood and Adolescence

Genetic factors influence vulnerability to common mental health conditions, but their role in early-life mental health remains understudied. We analysed genotype array and exome sequence data from two...

www.medrxiv.org

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Reposted by Hilary Martin

Chris Wallace @chr1sw.bsky.social · Jul 2

Is anyone aware of PhD students having access to #allofus data? We are being told it's impossible. Which seems... impractical... given that students do so much of the research in many places. Please reskeet even if you don't know the answer? Would really like to resolve this barrier for my student.

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Reposted by Hilary Martin

Olivia Wootton @olivia-wootton.bsky.social · Jul 3

A key methodological advantage is the use of Mendelian imputation to recover missing parental genotypes. This helps mitigate bias associated with non-random ascertainment of genotyped trios in these cohorts, over and above boosting power for association testing (See Extended Data Figure 1 and 2).

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Reposted by Hilary Martin

Olivia Wootton @olivia-wootton.bsky.social · Jul 3

I’m most excited about our rare variant findings: a higher burden of deleterious protein-truncating variants is associated with increased mental health symptoms. Trio models indicated direct genetic effects on externalising in MCS and on internalising symptoms in ALSPAC.

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Reposted by Hilary Martin

Olivia Wootton @olivia-wootton.bsky.social · Jul 3

New preprint!🚨
"“The Contribution of Common and Rare Genetic Variation to Emotional and Behavioural Symptoms in Childhood and Adolescence” is out on medRxiv.
www.medrxiv.org/content/10.1...

Thread 👇

The Contribution of Common and Rare Genetic Variation to Emotional and Behavioural Symptoms in Childhood and Adolescence

Genetic factors influence vulnerability to common mental health conditions, but their role in early-life mental health remains understudied. We analysed genotype array and exome sequence data from two...

www.medrxiv.org

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Hilary Martin @hilarycmartin.bsky.social · Jul 3

New work from our group led by @olivia-wootton.bsky.social and ‪@emmaewade.bsky.social‬ combining new exome sequence with existing genotype data on birth cohorts to look common and rare variant contributions to early-life mental health. www.medrxiv.org/content/10.1...

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Reposted by Hilary Martin

PGC Africa @pgc-africa.bsky.social · Jun 23

🚨PGC Africa Monthly Meeting Alert!

We are delighted to have Dr @olivia-wootton.bsky.social from Dr @hilarycmartin.bsky.social's group @sangerinstitute.bsky.social join the 5th virtual PGCAfrica meeting of 2025

📆 26th June 2025
⏰ 2PM GMT|2PM WAT|3PM CAT|4PM EAT
📢 Details in the flyer

#PGCAfrica

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Hilary Martin @hilarycmartin.bsky.social · Jun 21

Thanks to all co-authors particularly co-first authors David van den Berg (Abdel's group), Wei Huang (Matt's group) and Daniel Malawsky (my group) - none of whom are yet on bluesky!

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Hilary Martin @hilarycmartin.bsky.social · Jun 21

Finally, importantly, we replicate (in aggregate) the new genes showing rare variant associations with FI in independent cohorts with direct measures of cognitive ability (ALSPAC, MCS) & show that the ones not previously linked with NDDs are enriched ~2.5-fold for de novo PTVs in 31k NDD patients.

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Hilary Martin @hilarycmartin.bsky.social · Jun 21

One cool finding: rare protein-truncating variants (PTVs) in CADPS2 are signif associated with *increased* EA (most genes show negative assocs) but no signal for FI. This is consistent with common variant findings at the same locus (Supp Note 7). Maybe a non-cognitive mechanism? Replication needed!

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Hilary Martin @hilarycmartin.bsky.social · Jun 21

We show that using measured+imputed FI gives more power in rare variant tests than using educational attainment (EA) on the same sample (26 versus 9 signif genes). (cont)

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Hilary Martin @hilarycmartin.bsky.social · Jun 21

Other new genes with signif rare associations include some excellent candidates (e.g. ROBO2, CHD9) and some wild-cards (DPP8, IPO9) - maybe some novel biology there? (cont)

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Hilary Martin @hilarycmartin.bsky.social · Jun 21

I'm most excited about the rare variant findings: 26 genes with associations to measured+imputed fluid intelligence (FI), of which only 5 would be found using measured FI alone. 14/26 are well-known neurodevelopmental disorder (NDD) genes (4-fold enrichment, p=8e-8). (cont)

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Hilary Martin @hilarycmartin.bsky.social · Jun 21

For a lay-language summary and FAQ containing additional context, see the Supp www.medrxiv.org/content/10.1.... Thanks to @ewanbirney.bsky.social for his help on this.

Imputation of fluid intelligence scores reduces ascertainment bias and increases power for analyses of common and rare variants

Studying the genetics of intelligence can help us understand the neurobiology of cognitive function and the aetiology of rare neurodevelopmental conditions. The largest previous genetic studies of int...

www.medrxiv.org

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Hilary Martin @hilarycmartin.bsky.social · Jun 21

New preprint - collab with the groups of @mehurles.bsky.social and @dr-appie.bsky.social. We imputed missing fluid intelligence test scores into ~170k @ukbiobank.bsky.social indivs & showed how this reduces bias and increases power for rare+common variant analyses. www.medrxiv.org/content/10.1...

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Hilary Martin @hilarycmartin.bsky.social · Jun 21

Thanks! Correlation between measured and imputed fluid intelligence (FI) score is 0.46, which we though was decent given the test-
retest correlation is only 0.6. Previous work showed that measured FI correlates about 0.55 with general cognitive ability.

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Hilary Martin @hilarycmartin.bsky.social · Jun 12

And critically the @genesandhealth.bsky.social PIs Richard Trembath, @sarahfiner.bsky.social‬ and David van Heel (QMUL) and all our community volunteers.

Hilary Martin @hilarycmartin.bsky.social · Jun 12

Credit to those who did most of the heavy lifting: Hye In Kim (Pfizer), Chris DeBoever (Maze), @yiorkala.bsky.social and Klaudia Walter in my group, Chen Li (BMS), Sahar Mozaffari (Maze), Kousik Kundu (AZ), @ben-meir-jacobs.bsky.social‬ (QMUL)....

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Hilary Martin @hilarycmartin.bsky.social · Jun 12

Delighted that the 'flagship' manuscript on our @genesandhealth.bsky.social 44k exomes (British Pakistanis & Bangladeshis) is now preprinted. Great academic-industry collaboration. Lots of new associations (mostly additive, a few recessive) and new insights into homoz knockouts & drug discovery.

Georgios (Yiorgos) Kalantzis @yiorkala.bsky.social · Jun 12

Preprint alert! 🚨
doi.org/10.1101/2025...

Our manuscript on Exome sequencing and analysis of 44,028 British South Asians, using @genesandhealth.bsky.social is now available at @medrxivpreprint.bsky.social!

We present several great results, and I’m thrilled to highlight the pieces I worked on:

Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity

Genes and Health (G&H) is a biomedical study of adult British-Pakistani and -Bangladeshi research volunteers enriched for autozygosity. We performed whole exome sequencing in 44,028 G&H participants, ...

doi.org

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Hilary Martin @hilarycmartin.bsky.social · May 26

#eshg2025 Tomorrow 11.45am in the Gold Plenary room, my postdoc Georgios Kalantzis will talk about rare recessive gene-based tests in the BrAVa consortium, followed by colleague Hye In Kim talking about rare homozygous knockouts in the British South Asian Genes & Health project.

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Hilary Martin @hilarycmartin.bsky.social · May 26

#eshg2025 Today at 2.15pm in Amber 2 I'll be presenting our work on developmental conditions in the 100,000 Genomes Project (Genomics England corporate session). Then at 5.15pm in the Auditorium I'll talk about recessive effects in rare & common disease (consanguinity session).

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Hilary Martin @hilarycmartin.bsky.social · May 20

I have the same problem. Presume they are running a bit late with getting it up there....

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