Genetic regulation of body size and morphology from adolescence to early adulthood

BASIC SCIENCE ARTICLE OPEN Gene ic egula ion o body size and mo phology om adolescence o ea ly adul hood Ka i Sil en oinen 1 ✉, Robe F. K uege 2 , Aline Jelenko ic 3 , Reijo Sund 4 , Glenn I. Roisman 5 , Jaakko Kap io 6 and Ma McGue 2 © The Au ho (s) 2025 BACKGROUND: We analyzed he sha ed gene ic backg ound o ex ensi e an h opome ic measu emen s, de e mining body size and mo phology. METHODS: An h opome ic measu emen s we e aken o 15 ai s om 1512 US wins a an a e age age o 11.7 yea s (Minneso a, 51% emales) and o 20 ai s a an a e age age o 14.8 yea s o males (N=624) and 18.1 yea s o emales (N=505). Gene ic win modeling was u ilized o es ima e he gene ic co ela ions be ween hese ai s. RESULTS: In mid o la e adolescence, high gene ic co ela ions we e ound wi hin heigh - ela ed ai s and oo leng h ( A = 0.58–1.00) as well as wi hin adiposi y- ela ed ai s ( A =0.70–0.96), excep o skin old hicknesses. Gene ic co ela ions o c anio acial measu emen s we e smalle ( A =0.26–0.80). Howe e , almos all ai s showed some gene ic co ela ions wi h o he ai s, mos o which we e a leas mode a e ( A > 0.30). Resul s om ea lie assessmen s in ea ly adolescence wi h ewe ai s bu a la ge sample size we e la gely simila . Gene ic co ela ions be ween he ini ial and ollow-up assessmen s we e high ( A = 0.68–0.95), excep o c anio acial ai s, which showed somewha lowe co ela ions ( A =0.40–0.87). CONCLUSIONS: Sha ed gene ic a ia ion plays a significan ole in human body size and mo phology as well as hei de elopmen du ing adolescence. Pedia ic Resea ch; h ps://doi.o g/10.1038/s41390-025-04259-8 IMPACT: ●The e a e clus e s o an h opome ic ai s showing high gene ic co ela ions. ●The highes gene ic co ela ions we e ound wi hin heigh - and adiposi y- ela ed ai s. ●Nea ly all an h opome ic ai s sha e some gene ic a ia ion. ●Gene ic ac o s impo an ly con ibu e o he g ow h o all ai s du ing adolescence. ●Pleio opic e ec s a e impo an o unde s anding he gene ic egula ion o human physique. INTRODUCTION An h opome ic measu emen s a e an essen ial pa o child heal h check-ups, as abno mal alues can signal p oblems anging om inadequa e nu i ion 1 o se ious heal h condi ions. 2 Unde - s anding he gene ic egula ion o g ow h is impo an o iden i ying en i onmen al and medical issues ha may hinde heal hy de elopmen . Ex ensi e win and genome-wide associa- ion (GWA) s udies ha e e ealed significan associa ions o gene ic ac o s wi h heigh 3,4 and BMI a ia ion. 5,6 Addi ionally, gene ic influences ha e also been shown o o he an h opo- me ic ai s, such as wais 7 and ches ci cum e ence, 8 skin old hicknesses, 9 and c anio acial measu emen s. 10 The same gene ic ac o s la gely influence heigh and BMI h oughou childhood and adolescence, 11 and he ole o gene ic ac o s has also been demons a ed o he de elopmen o head 12 and ches ci cum e ence. 8 While p e ious s udies ha e highligh ed he impo ance o gene ic ac o s in g ow h, mos ha e ocused on heigh and BMI. E idence o many an h opome ic ai s is s ill lacking, pa icula ly in e ms o longi udinal change. Despi e ex ensi e gene ic esea ch on an h opome ic ai s, less is s ill known abou hei sha ed gene ic backg ound. Ea ly s udies ha e iden ified co ela ion pa e ns among a ious an h opome ic ai s, 13 sugges ing pa ially co ela ed gene ic componen s ha a ec di e en body pa s. La e win s udies ha e ound gene ic co ela ions be ween BMI and wais ci cum- e ence 7 as well as skin old hicknesses. 14,15 Some gene ically in o ma i e s udies ha e also explo ed gene ic co ela ions among a la ge numbe o an h opome ic ai s. S udies using wo- gene a ion amily da a om ou popula ions (one om India and h ee om Eu ope) ound mode a e gene ic co ela ions be ween Recei ed: 2 Decembe 2024 Re ised: 10 Ap il 2025 Accep ed: 16 June 2025 1 Helsinki Ins i u e o Demog aphy and Popula ion Heal h, Uni e si y o Helsinki, Helsinki, Finland. 2 Depa men o Psychology, Uni e si y o Minneso a Twin Ci ies, Minneapolis, MI, USA. 3 Depa men o Gene ics, Physical An h opology and Animal Physiology, Facul y o Science and Technology, Uni e si y o he Basque Coun y (UPV/EHU), Bilbao, Spain. 4 Ins i u e o Clinical Medicine, Uni e si y o Eas e n Finland, Kuopio, Finland. 5 Ins i u e o Child De elopmen , Uni e si y o Minneso a Twin Ci ies, Minneapolis, MI, USA. 6 Ins i u e o Molecula Medicine Finland (FIMM), HiLIFE, Uni e si y o Helsinki, Helsinki, Finland. ✉email: ka i.sil en oinen@helsinki.fi www.na u e.com/p 1234567890();,: c anio acial measu es 16,17 and high gene ic co ela ions be ween adiposi y- ela ed measu es. 18 Addi ionally, a s udy o Po uguese wins e ealed e y high gene ic co ela ions be ween adiposi y- ela ed measu es. 19 Howe e , hese s udies also ound weake ye s ill significan gene ic co ela ions o adiposi y- ela ed measu es wi h heigh 18,19 and c anio acial ai s. 16 Collec i ely, hese s udies sugges ha while he e a e clus e s o an h opome ic ai s wi h high gene ic co ela ions, nea ly all body pa s sha e some gene ic a ia ion. A limi a ion in p e ious s udies on gene ic co ela ions among an h opome ic measu es is ha age a ia ion may ha e a ec ed esul s, as pa ly di e en gene ic ac o s a ec human body pa s a di e en ages. 11 Fu he mo e, hese s udies lack longi udinal measu es ha would allow s udying he ole o gene ic ac o s in g ow h. In his s udy, we will p esen comp ehensi e analyses o he gene ic backg ound o human body size and mo phology assessed using 20 an h opome ic measu es, using he win design. Addi ionally, we will analyze how gene ic ac o s con ibu e o he g ow h o 15 o hese ai s. DATA AND METHODS The s udy coho was de i ed om he Minneso a Twin Family S udy (MTFS) as desc ibed p e iously. 20 In summa y, he coho consis ed o same-sex wins bo n in he USA, Minneso a, be ween 1972 and 1984, iden ified h ough Minneso a s a e eco ds. Con ac in o ma ion was a ailable o 1695 male and 1729 emale wins, and a ound 80% o hese wins comple ed an in-pe son in ake assessmen . The wins ep esen ed he Minneso a popula- ion a he ime, wi h 95% o hem being non-Hispanic whi e and he majo i y ha ing No he n Eu opean ances y. The ini ial an h opome ic assessmen was conduc ed when he child en had a mean age o 11.7 yea s ( anging om 10.7 o 12.8 yea s) and included 1512 win child en (51% gi ls), comp ising 252 male MZ, 233 emale MZ, 124 male DZ, and 147 emale DZ comple e win pai s. Measu emen s o 15 an h opome ic ai s we e conduc ed ollowing a specific measu emen p o ocol (Supplemen a y Table S1): ou measu emen s o body heigh (heigh , si ing heigh , knee heigh , and bu ock-knee heigh ), he leng h o bo h ee , fi e measu es o he head (head ci cum e - ence, head b ead h, ace heigh , and wo measu es o head leng h), weigh , a m ci cum e ence, and wais ci cum e ence bo h elaxed and sucking. Addi ionally, we calcula ed body mass index (BMI) by di iding weigh in kilog ams by he squa e o heigh in me e s (kg/m 2 ). Due o he skewed dis ibu ions o weigh , BMI, and wais ci cum e ence, we used he loga i hmic ans o ma ion o no malize hem. Fu he mo e, we adjus ed he ai s o he exac age sepa a ely o boys and gi ls, as he age e ec was s a is ically significan o nea ly all measu es (Supplemen a y Table S2). The ollow-up assessmen was conduc ed o 624 males wi h an a e age age o 14.8 yea s old ( anging om 13.6 o 16.9 yea s) and o 508 emales wi h an a e age age o 18.1 yea s old ( anging om 16.6 o 20.3 yea s), including 207 male MZ, 161 emale MZ, 104 male DZ and 93 emale DZ comple e pai s. The ollow-up assessmen included all measu es om he ini ial assessmen , as well as h ee b ead h measu emen s (shoulde , w is , and hip) and wo skin old measu es (biceps and iceps) (Supplemen a y Table S1). Weigh , BMI, wais ci cum e ence, and skin old measu emen s we e no malized using loga i hmic ans o ma ion due o skewed dis ibu ions. Nea ly all an h opome ic ai s showed a s ong age e ec in males bu no in emales because o hei olde age a he ime o ollow-up assessmen (Supplemen- a y Table S2). Howe e , o ensu e sys ema ic esul s, we adjus ed all ai s o age. The age adjus men s we e made by calcula ing eg ession esiduals using exac age as an independen a iable sepa a ely in he ini ial and ollow-up assessmen s and in males and emales. Addi ionally, we conduc ed a ac o analysis sepa a ely o bo h assessmen s and sexes using he p incipal ac o es ima o and Va imax o a ion o analyze he unde lying co ela ion s uc u e. These analyses and all desc ip i e esul s we e pe o med using S a a/MP 18.0 o Windows. Twin modeling was used o analyze he ole o gene ic ac o s in he a ia ion and co- a ia ion o an h opome ic ai s. 21 This echnique is based on he p inciple ha while MZ wins a e i ually gene ically iden ical a he gene sequence le el, DZ wins sha e, on a e age, hal o hei seg ega ing genes, like o dina y siblings. Since he co ela ion s uc u e be ween co- wins is known, i is possible o decompose ai a iance in o gene ic and en i onmen al componen s. Addi i e gene ic a iance (A; co ela ion 1 wi hin MZ and 0.5 wi hin DZ pai s) includes he e ec s o all loci influencing he ai . Sha ed en i onmen al a iance (C; co ela ion 1 wi hin bo h MZ and DZ pai s) encompasses he e ec s o all en i onmen al ac o s ha make co- wins simila . Unique en i onmen al a ia ion (E; co ela ion 0 wi hin bo h MZ and DZ wins) includes he e ec s o all en i onmen al ac o s ha make co- wins dissimila , including measu emen e o . Based on co- win co ela ions (Supplemen a y Table S3), we selec ed he addi i e gene ic/sha ed en i onmen /unique en i - onmen (ACE) model as ou baseline model. Model fi s a is ics a e p esen ed in Supplemen a y Table S4. To es he assump ions o win modeling, we compa ed he ACE model o he sa u a ed model, which es ima es all possible mean, a iance, and co a iance s a is ics wi hou assump ions. The ACE models showed sa is ac o y fi : 11 ai s had poo e fi compa ed o he sa u a ed model a a con en ional p- alue o 0.05 and ou ai s (head b ead h, ace heigh , and BMI in he ini ial assessmen and head b ead h in he ollow-up assessmen s) a a Bon e oni co ec ed significance le el (p< 0.001 using 37 es s). Sha ed en i onmen al ac o s we e s a is ically significan o 14 ai s a a p- alue o 0.05, and o ou ai s a he Bon e oni co ec ed significance le el (p< 0.001). Gi en ha mos ai s exhibi ed sex di e ences, we s a ified he models by sex. Using uni a ia e models, we ini ially calcula ed he p opo ions o a ia ion explained by addi i e gene ic ac o s (a 2 )–i.e., (na ow sense) he i abili y es ima es –as well as sha ed en i onmen al (c 2 ) and unique en i onmen al ac o s (e 2 ). Subsequen ly, we u ilized Cholesky decomposi ion, a model- ee me hod o decompose all a ia ion and co a ia ion in he da a in o unco ela ed la en ac o s. 22 This me hod was used o decompose he co a ia ion be ween he an h opome ic measu es in o gene ic and en i on- men al co a iances. S anda dizing hese co a iances p o ides es ima es o addi i e gene ic and unique en i onmen al co ela- ions. Since all ai s showed some e idence o sha ed en i on- men al a iance, we u ilized he ACE model e en when sha ed en i onmen al componen s we e no s a is ically significan . Howe e , in bi a ia e models, we ini ially es ima ed he addi i e gene ic co ela ions using he AE model and hen confi med hem using he ACE model. This app oach was used because he sha ed en i onmen al co ela ions could no be accu a ely calcula ed due o he small size o sha ed en i onmen al a ia ion. The gene ic win modeling was conduc ed using he OpenMx package, e sion 3.0.2, o R s a is ical so wa e. The pa ame e s we e es ima ed using he linea s uc u al equa ions me hodology and u ilizing he maximum likelihood es ima o . 23 RESULTS Table 1p esen s he desc ip i e s a is ics o he an h opome ic ai s in he ini ial and ollow-up assessmen s. G ow h was obse ed in all ai s be ween he assessmen s. The ela i e g ow h was lowes o he head- ela ed ai s (2–3%) and highes o he adiposi y- ela ed ai s (weigh , BMI, a m ci cum e ence, and wais ci cum e ence; 15–49%). In he ini ial assessmen , he measu es we e oughly simila in boys and gi ls. In he ollow-up K. Sil en oinen e al. 2 Pedia ic Resea ch assessmen s, he alues a e no compa able due o he age di e ence. Table 2p esen s he ela i e a iance componen s o gene ic and en i onmen al ac o s. Addi i e gene ic ac o s explained a significan p opo ion o he a ia ion in all an h opome ic ai s, wi h he i abili y es ima es gene ally lowe o c anio acial ai s (a 2 anged be ween 0.21 and 0.85) compa ed o he o he ai s (a 2 anged be ween 0.23 and 0.90). Sha ed en i onmen al ac o s also con ibu ed o he a ia ion in mos ai s (c 2 anged be ween 0.00 and 0.63), al hough he sha ed en i onmen al a iances we e no s a is ically significan o many ai s. The e we e no consis en di e ences in he he i abili y es ima es be ween males and emales. In gene al, sha ed en i onmen al ac o s explained mo e and addi i e gene ic ac o s less o he ai a ia ion in he ollow- up han in he ini ial assessmen . A e comple ing he uni a ia e analyses, we p oceeded o analyze he mu ual co ela ions be ween he ai s in he ini ial assessmen . Fac o analysis e ealed h ee ac o s in bo h males and emales: he fi s ac o eflec ed linea ai s (heigh - ela ed ai s and oo -leng h), he second ac o eflec ed olume ai s (BMI, a m ci cum e ence, and wais ci cum e ence), and he hi d ac o eflec ed c anio acial ai s ( he ac o analyses a ailable in Supplemen a y Table S5, he ai co ela ions in Supplemen a y Fig. S1, and hei 95% CIs in Supplemen a y Table S6). Howe e , all ai s showed some loading on all h ee ac o s. Nex , we decomposed he ai co ela ions in o gene ic and unique en i onmen al co ela ions. Figu e 1p esen s he addi i e gene ic co ela ions o boys (uppe diagonal ma ix) and gi ls (lowe diagonal ma ix) (95% CIs a e a ailable in Supplemen a y Table S7). Two clus e s o gene ic co ela ions we e iden ified: he compo- nen s o heigh and oo leng h exhibi ed high gene ic co ela- ions ( A =0.69–1.00), as did he adiposi y- ela ed ai s ( A =0.85–0.98). Howe e , mos o he gene ic co ela ions we e mode a e ( A ≥0.30) indica ing ha all ai s sha ed some gene ic a ia ion. Since hese co ela ions may be influenced by sha ed en i onmen al ac o s, we ecalcula ed hem allowing sha ed en i onmen al co ela ions (Supplemen a y Table S8). Howe e , he changes we e gene ally modes , and, in some cases, he co ela ions inc eased. Sha ed en i onmen al co ela ions could no be eliably es ima ed, and 95% CIs we e e y b oad, anging o many ai pai s om −1.00 o 1.00 (Supplemen a y Table S9). We also iden ified he unique en i onmen al co ela ions be ween he ai s, bu hey we e lowe han he addi i e gene ic co ela ions (Supplemen a y Fig. S2; 95% confidence in e als a e p esen ed in Supplemen a y Table S10). We epea ed he analyses using he mo e comp ehensi e an h opome ic measu emen s a ailable in he ollow-up assess- men . Gene ally, he esul s aligned wi h hose om he ini ial assessmen . In he ac o analysis, we iden ified h ee ac o s in bo h males and emales: he fi s ac o eflec ed olume ai s, he second ac o eflec ed linea ai s, and he hi d ac o eflec ed c anio acial ai s ( he ac o analysis is a ailable in Supplemen a y Table S11, he ai co ela ion in Supplemen a y Fig. S3, and hei 95% CIs in Supplemen a y Table S12). Figu e 2p esen s he addi i e gene ic co ela ions o boys (uppe diagonal ma ix) and gi ls (lowe diagonal ma ix) (95% CIs a e p esen ed in Supple- men a y Table S13). We obse ed clus e s o gene ic co ela ions wi hin he heigh - ela ed ai s and oo -leng h ( A =0.58–1.00) and adiposi y- ela ed ai s ( A =0.70–0.96). Howe e , skin old hicknesses exhibi ed only mode a e gene ic co ela ions wi h he adiposi y- ela ed ai s ( A =0.26–0.50), and he co ela ions wi h o he ai s we e close o ze o. C anio acial ai s showed somewha weake mu ual co ela ions ( A =0.26–0.80), and hey also had mode a e gene ic co ela ions ( A ≥0.30) wi h heigh - Table 1. Desc ip i e s a is ics o age and an h opome ic ai s in he ini ial and ollow-up assessmen s by sex. Ini ial assessmen Follow-up assessmen Male Female Male Female mean SD mean SD mean SD mean SD Age yea s 11.7 0.39 11.7 0.46 14.8 0.49 18.3 0.71 Heigh cm 149 7.02 151 7.31 170 7.85 166 6.4 Si ing heigh cm 77.1 3.48 78.2 4.12 86.8 4.47 87.1 3.25 Knee heigh cm 46.7 2.84 46.8 2.77 52.9 2.85 50.5 2.63 Bu ock-knee leng h cm 51.7 3.23 52.7 3.44 59.1 3.34 58.4 2.94 Foo leng h le cm 23.0 1.42 22.5 1.31 25.7 1.38 23.5 1.25 Foo leng h igh cm 23.1 1.38 22.5 1.32 25.7 1.37 23.6 1.25 Head ci cum e ence cm 54.1 1.62 54.1 1.75 55.9 1.68 55.5 1.75 Head b ead h cm 14.4 0.48 14.3 0.50 14.9 0.53 14.6 0.52 Face heigh cm 20.7 1.09 20.0 1.12 21.8 1.07 20.8 1.03 Head leng h 1 cm 18.6 0.70 18.3 0.81 19.0 0.84 18.8 0.82 Head leng h 2 cm 16.8 0.86 16.4 0.95 17.3 0.95 17.2 0.84 Weigh kg 41.3 9.53 44.5 11.26 61.7 13.03 65.2 14.73 BMI kg/m 2 18.4 3.22 19.4 3.73 21.2 3.58 23.7 4.91 A m ci cum e ence cm 21.8 2.88 22.6 3.24 25.9 3.29 26.6 3.67 Wais ci c. elaxed cm 65.7 9.00 67.2 9.74 76.2 9.17 78.5 11.28 Wais ci c. sucking cm 60.6 8.87 62.6 9.90 71.1 9.69 73.2 11.31 Shoulde b ead h cm NA NA NA NA 33.8 3.07 34.2 2.88 W is b ead h cm NA NA NA NA 5.56 0.33 5.18 0.33 Hip b ead h cm NA NA NA NA 30.4 3.03 34.3 3.17 Biceps skin old mm NA NA NA NA 8.19 5.93 11.73 6.71 T iceps skin old mm NA NA NA NA 13.3 8.30 20.1 7.89 K. Sil en oinen e al. 3 Pedia ic Resea ch Table 2. Rela i e a iance componen s o addi i e gene ic, sha ed en i onmen al, and unique en i onmen al ac o s o an h opome ic ai s by sex. Males Females Addi i e gene ic ac o s Sha ed en i onmen al ac o s Unique en i onmen al ac o s Addi i e gene ic ac o s Sha ed en i onmen al ac o s Unique en i onmen al ac o s a 2 95% CI c 2 95% CI e 2 95% CI a 2 95% CI c 2 95% CI e 2 95% CI LL UL LL UL LL UL LL UL LL UL LL UL Ini ial assessmen Heigh 0.78 0.57 0.94 0.15 0.00 0.36 0.07 0.06 0.09 0.71 0.54 0.93 0.22 0.00 0.40 0.07 0.05 0.08 Si ing heigh 0.75 0.52 0.88 0.11 0.00 0.34 0.14 0.11 0.17 0.67 0.49 0.90 0.23 0.00 0.42 0.10 0.08 0.12 Knee heigh 0.81 0.60 0.94 0.11 0.00 0.32 0.07 0.06 0.09 0.73 0.53 0.91 0.17 0.00 0.37 0.10 0.08 0.12 Bu ock-knee leng h 0.39 0.22 0.61 0.44 0.22 0.60 0.17 0.14 0.21 0.73 0.53 0.89 0.14 0.00 0.34 0.13 0.10 0.16 Foo leng h le 0.82 0.60 0.92 0.08 0.00 0.30 0.09 0.08 0.12 0.66 0.47 0.89 0.23 0.00 0.42 0.11 0.09 0.14 Foo leng h igh 0.83 0.61 0.93 0.09 0.00 0.31 0.08 0.07 0.10 0.64 0.45 0.88 0.23 0.00 0.42 0.13 0.10 0.16 Head ci c 0.49 0.30 0.74 0.35 0.09 0.53 0.17 0.14 0.21 0.84 0.61 0.88 0.01 0.00 0.24 0.15 0.12 0.18 Head b ead h 0.73 0.49 0.84 0.08 0.00 0.31 0.20 0.16 0.24 0.73 0.53 0.89 0.14 0.00 0.33 0.13 0.11 0.17 Head leng h 1 0.58 0.34 0.80 0.19 0.00 0.41 0.24 0.19 0.29 0.67 0.43 0.81 0.11 0.00 0.34 0.23 0.18 0.28 Head leng h 2 0.53 0.31 0.81 0.26 0.00 0.48 0.21 0.17 0.25 0.48 0.29 0.71 0.34 0.12 0.52 0.18 0.15 0.23 Face heigh 0.30 0.07 0.62 0.37 0.03 0.61 0.34 0.28 0.40 0.41 0.10 0.65 0.17 0.00 0.45 0.42 0.35 0.50 Weigh 0.79 0.59 0.92 0.12 0.00 0.32 0.09 0.07 0.11 0.78 0.59 0.93 0.14 0.00 0.33 0.08 0.06 0.10 BMI 0.79 0.59 0.92 0.12 0.00 0.32 0.09 0.07 0.11 0.82 0.63 0.93 0.10 0.00 0.29 0.08 0.07 0.10 A m ci c 0.76 0.55 0.90 0.11 0.00 0.32 0.12 0.10 0.15 0.83 0.62 0.92 0.07 0.00 0.28 0.10 0.08 0.12 Wais ci c. elax 0.55 0.36 0.78 0.30 0.07 0.48 0.15 0.12 0.19 0.65 0.45 0.86 0.19 0.00 0.39 0.15 0.12 0.19 Wais ci c. sucking 0.68 0.47 0.87 0.17 0.00 0.38 0.15 0.12 0.19 0.68 0.48 0.88 0.18 0.00 0.38 0.14 0.11 0.17 Follow-up assessmen Heigh 0.65 0.44 0.90 0.24 0.00 0.46 0.11 0.09 0.14 0.78 0.54 0.95 0.17 0.00 0.41 0.06 0.04 0.07 Si ing heigh 0.67 0.44 0.88 0.18 0.00 0.41 0.15 0.12 0.19 0.87 0.83 0.90 0.00 0.00 0.19 0.13 0.10 0.17 Knee heigh 0.62 0.41 0.88 0.24 0.00 0.45 0.13 0.11 0.17 0.70 0.41 0.85 0.11 0.00 0.39 0.19 0.15 0.25 Bu ock-knee leng h 0.46 0.26 0.71 0.37 0.12 0.56 0.17 0.14 0.22 0.63 0.35 0.84 0.18 0.00 0.45 0.19 0.15 0.25 Foo leng h le 0.69 0.45 0.86 0.14 0.00 0.38 0.17 0.13 0.21 0.90 0.87 0.92 0.00 0.00 0.19 0.10 0.08 0.13 Foo leng h igh 0.67 0.44 0.87 0.17 0.00 0.40 0.16 0.13 0.20 0.88 0.85 0.91 0.00 0.00 0.27 0.12 0.09 0.15 Head ci c 0.57 0.35 0.84 0.25 0.00 0.47 0.18 0.14 0.22 0.85 0.80 0.88 0.00 0.00 0.27 0.15 0.12 0.20 Head b ead h 0.67 0.44 0.85 0.15 0.00 0.38 0.18 0.14 0.22 0.84 0.79 0.88 0.00 0.00 0.24 0.16 0.12 0.21 Head leng h 1 0.43 0.21 0.72 0.35 0.06 0.56 0.22 0.18 0.27 0.44 0.13 0.73 0.23 0.00 0.50 0.33 0.26 0.42 Head leng h 2 0.37 0.17 0.63 0.43 0.17 0.62 0.20 0.16 0.25 0.54 0.22 0.73 0.12 0.00 0.41 0.34 0.27 0.43 Face heigh 0.21 0.00 0.53 0.42 0.11 0.64 0.37 0.30 0.46 0.65 0.29 0.73 0.01 0.00 0.35 0.34 0.27 0.43 Shoulde b ead h 0.27 0.10 0.48 0.55 0.34 0.70 0.19 0.15 0.24 0.23 0.09 0.41 0.63 0.45 0.77 0.14 0.11 0.18 W is b ead h 0.64 0.38 0.82 0.14 0.00 0.38 0.22 0.18 0.28 0.61 0.31 0.82 0.17 0.00 0.46 0.22 0.17 0.28 Weigh 0.71 0.50 0.91 0.19 0.00 0.40 0.10 0.08 0.12 0.71 0.47 0.91 0.18 0.00 0.42 0.11 0.09 0.15 BMI 0.77 0.55 0.91 0.12 0.00 0.34 0.11 0.09 0.14 0.62 0.40 0.89 0.26 0.00 0.48 0.12 0.09 0.16 A m ci c 0.79 0.56 0.91 0.10 0.00 0.33 0.12 0.09 0.15 0.67 0.39 0.83 0.11 0.00 0.38 0.22 0.17 0.29 K. Sil en oinen e al. 4 Pedia ic Resea ch ela ed and adiposi y- ela ed ai s. When we es ima ed he addi i e gene ic co ela ions while allowing o sha ed en i on- men al co ela ions, he changes we e gene ally modes and in some cases he co ela ions inc eased (Supplemen a y Table S14). In alignmen wi h he ini ial assessmen , he sha ed en i onmen al co ela ions could no be eliably es ima ed (Supplemen a y Table S15). Unique en i onmen al co ela ions we e lowe han addi i e gene ic co ela ions (Supplemen a y Fig. S4; 95% confidence in e als a e p esen ed in Supplemen a y Table S16). Finally, we examined he co ela ions o an h opome ic ai s be ween he ini ial and ollow-up assessmen s (Table 3). The ai co ela ions anged om 0.34 o 0.90. Co ela ions o ace heigh and leng h we e lowe han o o he ai s, bu no sys ema ic di e ences we e obse ed o he wise. Addi i e gene ic co ela- ions we e consis en ly highe , while unique en i onmen al co ela ions we e lowe han he ai co ela ions. DISCUSSION In his comp ehensi e s udy o human body size and mo phology, we obse ed ha gene ic ac o s explained a majo p opo ion o he a ia ion in 21 an h opome ic ai s. Fo heigh and BMI, he he i abili y es ima es we e high, showing ha be ween 62% o 82% o he a ia ion is explained by gene ic di e ences. Howe e , sha ed en i onmen al ac o s also explained a po ion o he a ia ion in nea ly all an h opome ic ai s. The e was also some e idence ha he p opo ion o sha ed en i onmen al a ia ion inc eased om he ini ial o he ollow-up assessmen . This esul is di e en han wha was ound in la ge-scale win s udies on heigh 3 and BMI, 5 sugges ing ha sha ed en i onmen al a ia ion ends o dec ease om childhood o adolescence. Howe e , he e is a lack o s udies on o he an h opome ic measu es a di e en ages, and he CIs o sha ed en i onmen al a iance in ou s udy we e wide. Di e en ia - ing be ween sha ed en i onmen al ac o s and gene ic ac o s equi es conside able s a is ical powe , 24 o en leading o he neglec o sha ed en i onmen al ac o s in gene ic win s udies. These esul s sugges ha sha ed en i onmen al ac o s can a ec he a ia ion o an h opome ic ai s along wi h gene ic ac o s and should be be e ecognized in u u e s udies. In e es ingly, he he i abili y es ima es o c anio acial ai s we e consis en ly lowe compa ed o heigh - and adiposi y- ela ed ai s, sugges ing ha en i onmen al ac o s unique o indi iduals may play a ole in shaping acial ea u es. P e ious s udies using pedig ee da a ha e epo ed he i abili y es ima es o c anio acial measu es a a simila le el o hose in ou s udy. 16,25 Howe e , measu emen e o is also included in unique en i onmen al a ia ion, which can explain he lowe he i abili y o hese ai s. Fo 16 o hese 21 ai s, we had longi udinal measu es ha allowed us o examine ac o s ela ed o g ow h o e adolescence, om abou 11 yea s onwa d. As expec ed, he e was subs an ial g ow h o heigh - and adiposi y- ela ed ai s, bu minimal g ow h o c anio acial ai s, eflec ing he no mal physical de elopmen o child en du ing adolescence. 26 Gene ic co ela- ions o heigh - and adiposi y- ela ed ai s we e high, indica ing ha a la ge p opo ion o he gene ic ac o s a ec ing hese ai s du ing pube y a e he same. These gene ic co ela ions we e e y simila o hose ound o heigh and BMI du ing adolescence in a p e ious la ge-scale win s udy ha pooled da a om se e al win coho s. 11 Fo c anio acial ai s, he gene ic co ela ions we e lowe han o o he ai s, sugges ing ha pa ly di e en se s o gene ic ac o s begin o shape he head du ing adolescence. These esul s indica e ha he gene ic egula ion o di e en pa s o he body can a y o e he cou se o aging. Howe e , i is no ewo hy ha he e can be mo e measu emen e o in c anio acial han in o he measu emen s, which can also lead o lowe gene ic co ela ions. We iden ified h ee clus e s o gene ic co ela ions. Fi s ly, heigh - ela ed measu es and he leng h o bo h ee exhibi ed Table 2. con inued Males Females Addi i e gene ic ac o s Sha ed en i onmen al ac o s Unique en i onmen al ac o s Addi i e gene ic ac o s Sha ed en i onmen al ac o s Unique en i onmen al ac o s a 2 95% CI c 2 95% CI e 2 95% CI a 2 95% CI c 2 95% CI e 2 95% CI LL UL LL UL LL UL LL UL LL UL LL UL Hip b ead h 0.59 0.40 0.84 0.31 0.06 0.50 0.11 0.08 0.13 0.48 0.27 0.78 0.36 0.07 0.57 0.16 0.12 0.21 Wais ci c. elax 0.61 0.39 0.85 0.22 0.00 0.44 0.18 0.14 0.22 0.83 0.78 0.87 0.00 0.00 0.27 0.17 0.13 0.22 Wais ci c. sucking 0.49 0.27 0.77 0.31 0.06 0.52 0.20 0.16 0.26 0.45 0.21 0.77 0.35 0.03 0.58 0.20 0.16 0.26 Biceps skin old 0.57 0.36 0.84 0.26 0.00 0.46 0.17 0.13 0.21 0.15 0.00 0.41 0.60 0.35 0.76 0.25 0.19 0.32 T iceps skin old 0.42 0.23 0.67 0.40 0.16 0.58 0.18 0.14 0.22 0.24 0.00 0.54 0.47 0.19 0.68 0.30 0.23 0.38 K. Sil en oinen e al. 5 Pedia ic Resea ch high gene ic co ela ions. La ge GWA s udies 27 and whole- genome s udies 28 ha e iden ified nume ous genes associa ed wi h heigh . Genes con ibu ing o skele al g ow h and he de elopmen o ca ilage and connec i e issues a e en iched in hese s udies. Building on such gene ic findings, s udies using immo alized chond ogenic mu ine cell lines demons a ed ha genes associa ed wi h heigh a e exp essed highly in g ow h pla e chond ocy es. 27,29 Ou findings sugges ha pa ly he same gene ic ac o s egula e he ossifica ion o long bones and ee bones. The second clus e encompassed adiposi y- ela ed ai s, which ha e also shown high gene ic co ela ions in p e ious pedig ee 18 and win s udies. 19 E idence om GWA, win, and epidemiological s udies suppo s he idea ha ea ing beha io plays a significan ole in media ing he influences o gene ic ac o s on BMI. 30 The e o e, nu i ion p obably influences hese gene ic co ela ions. Howe e , unlike p e ious s udies, 18,19 ou s udy ound only mode a e gene ic co ela ions be ween skin old hicknesses and BMI/wais ci cum e ence. A p e ious GWA s udy indica ed ha gene ic a ian s linked o body a dis ibu ion a e associa ed wi h lipid me abolism and adipose issue egula ion. 31 I is possible ha hese gene ic e ec s a e mo e p onounced in adolescence, leading o dec eased gene ic co ela ions in ou da a. The hi d clus e in ol ed c anio acial ai s, bu he gene ic co ela ions among hem we e weake compa ed o heigh - and adiposi y- ela ed ai s. The gene ic complexi y o c anio acial ai s was also highligh ed in a ecen GWA s udy. 32 These esul s a e expec ed gi en he in ica e na u e o he head, which comp ises bo h so and bone issues likely influenced by dis inc gene ic ac o s. In addi ion o hese clus e s o gene ic co ela ions, we ound ha nea ly all ai s showed some sha ed gene ic a ia ion, as seen in p e ious s udies. The gene ic co ela ions we e gene ally highe han he ai co ela ions, indica ing ha mainly gene ic ac o s a e behind he an h opome ic co ela ions. These esul s a e no su p ising, as pleio opy is e y common in human ai s. 33 Howe e , he e can be se e al mechanisms behind pleio opic e ec s, 34 and we can only specula e on which ac o s explain hem in ou s udy. Since all body pa s a e o med by he same issues, he unde lying sha ed gene ic mechanisms ha egula e he g ow h and de elopmen o bone, adipose, and muscle issues can explain gene ic co ela ions be ween e en dis inc body pa s such as c anio acial and adiposi y- ela ed ai s. These gene ic co ela ions may ha e a backg ound in emb yonic de elopmen when di e en body pa s de elop om he same emb yonic s uc u es. 35 I is also possible ha he pos na al en i onmen , especially nu i ion, can a ec di e en ai s and explain hese gene ic co ela ions. 30 This is e iden o adiposi y- ela ed ai s bu may also explain co ela ions be ween heigh - and adiposi y- ela ed ai s. Disen angling hese di e en mechanisms equi es di e en s udy designs, such as combining de ailed measu es o po en ial en i onmen al ac o s wi h longi udinal an h opome ic measu es. Since we ound e idence o sha ed en i onmen al ac o s, we also s udied he sha ed en i onmen al co ela ions be ween 0.44 0.45 0.42 0.66 0.45 0.46 0.54 0.39 0.32 0.45 0.47 0.85 0.87 0.85 0.98 0.44 0.46 0.43 0.65 0.45 0.47 0.53 0.37 0.29 0.42 0.49 0.88 0.90 0.87 0.98 0.43 0.52 0.40 0.65 0.43 0.46 0.55 0.40 0.34 0.46 0.42 0.91 0.94 0.88 0.87 0.37 0.47 0.35 0.61 0.39 0.42 0.52 0.41 0.28 0.41 0.42 0.93 0.91 0.90 0.89 0.68 0.72 0.64 0.82 0.61 0.65 0.62 0.44 0.36 0.48 0.54 0.91 0.90 0.92 0.91 0.52 0.56 0.43 0.50 0.57 0.54 0.59 0.33 0.46 0.46 0.47 0.33 0.39 0.38 0.39 0.40 0.45 0.32 0.45 0.39 0.42 0.59 0.36 0.79 0.44 0.53 0.43 0.42 0.48 0.50 0.35 0.34 0.27 0.40 0.36 0.36 0.70 0.40 0.69 0.39 0.39 0.31 0.32 0.32 0.32 0.31 0.34 0.22 0.37 0.29 0.29 0.71 0.26 0.27 0.30 0.38 0.33 0.36 0.34 0.34 0.53 0.55 0.43 0.59 0.49 0.50 0.58 0.72 0.60 0.48 0.52 0.44 0.45 0.48 0.47 0.80 0.71 0.79 0.76 1.00 0.41 0.30 0.38 0.47 0.42 0.68 0.40 0.47 0.54 0.53 0.77 0.66 0.78 0.76 0.99 0.39 0.29 0.35 0.44 0.39 0.68 0.40 0.48 0.54 0.53 0.86 0.72 0.86 0.76 0.78 0.44 0.32 0.35 0.52 0.47 0.78 0.51 0.60 0.69 0.68 0.92 0.71 0.85 0.79 0.80 0.38 0.28 0.32 0.40 0.44 0.63 0.30 0.43 0.48 0.50 0.89 0.71 0.69 0.75 0.77 0.44 0.32 0.34 0.45 0.51 0.72 0.43 0.53 0.53 0.51 0.88 0.91 0.87 0.83 0.85 0.42 0.28 0.34 0.46 0.48 0.67 0.30 0.45 0.50 0.51 wais _C_suck wais _C_ elax a m_C BMI weigh ace_H head_L_2 head_L_1 head_B head_C oo _L_ igh oo _L_le bu ock_knee_L knee_H si ing_H o al_H o al_H si ing_H knee_H bu ock_knee_L oo _L_le oo _L_ igh head_C head_B head_L_1 head_L_2 ace_H weigh BMI a m_C wais _C_ elax wais _C_suck T ai T ai –1.0 –0.5 0.0 0.5 1.0 Co Fig. 1 Addi i e gene ic co ela ions o an h opome ic ai s in males (uppe diagonal ma ix) and emales (lowe diagonal ma ix) in he ini ial assessmen . B b ead h, C ci cum e ence, H heigh , L leng h. K. Sil en oinen e al. 6 Pedia ic Resea ch he ai s. Howe e , we ound ha he sha ed en i onmen al a iance componen s we e oo low o eliably es ima e hese co ela ions. The e o e, we canno de e mine i he e a e en i onmen al ac o s sha ed by co- wins ha a ec di e en an h opome ic ai s. We calcula ed all gene ic co ela ions while also accoun ing o sha ed en i onmen al influences, bu his had a modes e ec on he magni ude o gene ic co ela ions, and in some cases, hey e en inc eased. This suppo s he conclusion ha he gene ic co ela ions eflec a sha ed gene ic backg ound be ween he ai s a he han unspecified amilial e ec s combining sha ed gene ic and en i onmen al influences. Ou s udy has s eng hs and limi a ions. We ha e de ailed an h opome ic measu emen s in gene ically in o ma i e da a allowing us o analyze he gene ics o body mo phology in de ail. Addi ionally, we had longi udinal da a o se e al ai s, which enabled us o analyze how gene ic ac o s impac g ow h du ing adolescence. Ou da ase was no la ge enough o simul aneously es ima e gene ic and sha ed en i onmen al e ec s wi h su ficien powe . Howe e , we confi med ha sha ed en i onmen al ac o s had minimal impac on gene ic co ela ions. Ou main limi a ion is he lack o dual-ene gy X- ay abso p iome y (DEXA) o compu e omog aphy measu emen s, which would ha e allowed us o di ec ly measu e body composi ion. Likewise, magne ic esonance imaging (MRI) could be used o assess, o example, he bony s uc u e o he skull. This in o ma ion would ha e been aluable in analyzing he ex en o which di e en an h opome ic ai s sha e common gene ic a iance wi h body composi ion measu es. The popula ion o Minneso a du ing he da a collec ion pe iod was e hnically homogeneous. I is likely ha in mo e he e ogeneous popula ions, he i abili y es ima es would be lowe compa ed o his s udy, due o a la ge sha ed en i onmen al a ia ion. In conclusion, we ound ha sha ed gene ic ac o s b oadly a ec he body size and mo phology o humans. Clus e s o high gene ic co ela ions we e iden ified o heigh - and adiposi y- ela ed ai s, bu mos o he ai s sha ed some gene ic a ia ion. Gene ic ac o s also la gely explained he co ela ions o hese ai s o e adolescence. Pleio opic e ec s a e impo an o unde s anding he gene ic egula ion o human physique. 0.03 0.13 0.10 0.14 0.12 0.13 0.08 0.14 0.02 0.04 0.09 0.06 0.07 0.35 0.39 0.40 0.31 0.36 0.34 0.75 −0.01 0.10 0.03 0.13 0.07 0.08 0.12 0.12 0.05 0.14 0.09 0.09 0.06 0.35 0.40 0.36 0.20 0.38 0.31 0.85 0.18 0.22 0.28 0.55 0.33 0.31 0.41 0.31 0.23 0.32 0.26 0.35 0.48 0.89 0.89 0.90 0.78 0.96 0.51 0.49 0.21 0.24 0.31 0.54 0.36 0.34 0.40 0.28 0.29 0.33 0.27 0.34 0.48 0.88 0.87 0.86 0.74 0.97 0.52 0.49 0.30 0.40 0.39 0.60 0.42 0.40 0.36 0.34 0.28 0.34 0.20 0.38 0.44 0.87 0.83 0.81 0.71 0.69 0.48 0.46 0.18 0.26 0.28 0.55 0.29 0.28 0.40 0.33 0.30 0.34 0.23 0.30 0.48 0.90 0.93 0.67 0.82 0.81 0.48 0.49 0.05 0.19 0.18 0.45 0.24 0.23 0.38 0.34 0.27 0.35 0.17 0.40 0.49 0.92 0.93 0.70 0.88 0.85 0.50 0.50 0.43 0.50 0.51 0.71 0.52 0.51 0.48 0.34 0.35 0.46 0.32 0.46 0.61 0.90 0.89 0.77 0.87 0.86 0.43 0.45 0.43 0.43 0.41 0.52 0.49 0.50 0.31 0.28 0.20 0.36 0.27 0.21 0.59 0.43 0.53 0.56 0.38 0.42 0.12 0.14 0.26 0.28 0.39 0.24 0.32 0.33 0.29 0.15 0.08 0.28 0.24 0.49 0.51 0.36 0.41 0.47 0.31 0.35 0.08 0.15 0.43 0.48 0.41 0.38 0.42 0.42 0.49 0.26 0.45 0.43 0.41 0.45 0.63 0.47 0.54 0.48 0.45 0.51 0.19 0.21 0.39 0.48 0.36 0.33 0.39 0.36 0.61 0.33 0.72 0.60 0.37 0.41 0.57 0.47 0.49 0.33 0.42 0.46 0.18 0.23 0.29 0.31 0.26 0.33 0.32 0.27 0.69 0.28 0.80 0.51 0.28 0.30 0.38 0.31 0.32 0.19 0.25 0.27 0.04 0.10 0.09 0.19 0.10 0.12 0.16 0.17 0.60 0.32 0.33 0.45 0.23 0.32 0.44 0.37 0.39 0.29 0.30 0.35 0.09 0.13 0.34 0.43 0.33 0.34 0.39 0.39 0.65 0.75 0.65 0.59 0.40 0.41 0.58 0.47 0.48 0.44 0.47 0.49 0.14 0.17 0.77 0.69 0.78 0.69 1.00 0.42 0.30 0.33 0.44 0.54 0.47 0.65 0.62 0.32 0.37 0.50 0.42 0.44 0.08 0.10 0.76 0.69 0.78 0.69 0.99 0.44 0.29 0.33 0.41 0.51 0.45 0.63 0.62 0.33 0.39 0.48 0.43 0.44 0.06 0.08 0.78 0.58 0.81 0.72 0.70 0.50 0.28 0.35 0.47 0.57 0.45 0.50 0.70 0.40 0.46 0.53 0.57 0.59 0.20 0.25 0.90 0.70 0.86 0.76 0.78 0.38 0.23 0.26 0.37 0.45 0.43 0.47 0.56 0.20 0.27 0.40 0.37 0.39 0.04 0.09 0.84 0.61 0.63 0.64 0.66 0.50 0.39 0.35 0.53 0.61 0.57 0.56 0.70 0.39 0.49 0.53 0.40 0.44 0.08 0.13 0.85 0.89 0.86 0.78 0.79 0.47 0.32 0.30 0.42 0.56 0.50 0.56 0.63 0.24 0.34 0.48 0.39 0.42 0.08 0.12 iceps_SF biceps_SF wais _C_suck wais _C_ elax hip_B a m_C BMI weigh w is _B shoulde _B ace_H head_L_2 head_L_1 head_B head_C oo _L_ igh oo _L_le bu ock_knee_L knee_H si ing_H o al_H o al_H si ing_H knee_H bu ock_knee_L oo _L_le oo _L_ igh head_C head_B head_L_1 head_L_2 ace_H shoulde _B w is _B weigh BMI a m_C hip_B wais _C_ elax wais _C_suck biceps_SF iceps_SF T ai T ai –1.0 –0.5 0.0 0.5 1.0 Co Fig. 2 Addi i e gene ic co ela ions o an h opome ic ai s in males (uppe diagonal ma ix) and emales (lowe diagonal ma ix) in he ollow-up assessmen s. B b ead h, C ci cum e ence, H heigh , L leng h, SF skin old. K. Sil en oinen e al. 7 Pedia ic Resea ch DATA AVAILABILITY The da a a e eely a ailable o esea ch pu poses. Any inqui ies should be sen o Ma McGue ([email p o ec ed]). REFERENCES 1. No is, S. A. e al. Nu i ion in adolescen g ow h and de elopmen . Lance 399, 172–184 (2022). 2. Ha ju, S., Saa i, A., Sund, R. & Sankilampi, U. Epidemiology o diso de s associa ed wi h sho s a u e in childhood: a 20-yea bi h coho s udy in Finland. Clin. Epidemiol. 14, 1205–1214 (2022). 3. Jelenko ic, A. e al. Gene ic and en i onmen al influences on heigh om in ancy o ea ly adul hood: An indi idual-based pooled analysis o 45 win coho s. Sci. Rep. 6, 28496 (2016). 4. Yengo, L. e al. A sa u a ed map o common gene ic a ian s associa ed wi h human heigh . Na u e 610, 704–712 (2022). 5. Sil en oinen, K. e al. 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Gene ic and en i onmen al de e mina ion o acking in sub- cu aneous a dis ibu ion du ing adolescence. Am. J. Clin. Nu . 86, 652–660 (2007). Table 3. T ai co ela ions and addi i e gene ic and unique en i onmen al co ela ions be ween he an h opome ic ai s in ini ial and ollow-up assessmen s by sex. T ai co ela ion Addi i e gene ic co ela ion Unique en i onmen al co ela ion 95% CI A 95% CI E 95% CI LL UL LL UL LL UL Males Heigh 0.87 0.85 0.89 0.90 0.87 0.92 0.56 0.46 0.64 Si ing heigh 0.79 0.76 0.82 0.85 0.81 0.88 0.41 0.29 0.51 Knee heigh 0.80 0.77 0.83 0.85 0.82 0.88 0.37 0.26 0.48 Bu ock-knee leng h 0.79 0.76 0.82 0.86 0.82 0.9 0.36 0.24 0.47 Foo leng h le 0.81 0.78 0.84 0.87 0.83 0.9 0.41 0.29 0.51 Foo leng h igh 0.82 0.79 0.84 0.88 0.85 0.91 0.35 0.23 0.46 Head ci cum e ence 0.75 0.71 0.78 0.79 0.74 0.83 0.60 0.51 0.67 Head b ead h 0.87 0.85 0.89 0.93 0.91 0.95 0.60 0.52 0.68 Face heigh 0.48 0.41 0.54 0.64 0.54 0.73 0.12 0.00 0.24 Head leng h 1 0.65 0.60 0.69 0.75 0.69 0.81 0.30 0.18 0.42 Head leng h 2 0.45 0.38 0.51 0.49 0.39 0.57 0.27 0.15 0.39 Weigh 0.91 0.90 0.92 0.94 0.92 0.95 0.64 0.56 0.71 BMI 0.90 0.89 0.92 0.95 0.93 0.96 0.53 0.43 0.62 A m ci cum e ence 0.82 0.79 0.84 0.86 0.82 0.89 0.52 0.42 0.61 Wais ci c. elaxed 0.80 0.77 0.83 0.88 0.85 0.91 0.41 0.30 0.51 Wais ci c. sucking 0.75 0.72 0.79 0.84 0.79 0.88 0.37 0.25 0.48 Females Heigh 0.71 0.66 0.75 0.73 0.67 0.78 0.49 0.36 0.59 Si ing heigh 0.68 0.63 0.73 0.73 0.67 0.79 0.29 0.15 0.43 Knee heigh 0.70 0.65 0.74 0.78 0.72 0.83 0.13 -0.02 0.28 Bu ock-knee leng h 0.66 0.61 0.71 0.72 0.64 0.78 0.34 0.20 0.47 Foo leng h le 0.82 0.79 0.84 0.83 0.79 0.87 0.62 0.51 0.71 Foo leng h igh 0.81 0.78 0.84 0.85 0.81 0.89 0.46 0.33 0.57 Head ci cum e ence 0.72 0.67 0.76 0.77 0.70 0.82 0.40 0.26 0.52 Head b ead h 0.83 0.80 0.85 0.87 0.83 0.90 0.61 0.50 0.70 Face heigh 0.49 0.42 0.56 0.70 0.59 0.81 0.06 -0.09 0.21 Head leng h 1 0.51 0.44 0.57 0.59 0.48 0.68 0.29 0.15 0.42 Head leng h 2 0.34 0.26 0.42 0.40 0.27 0.51 0.23 0.08 0.37 Weigh 0.78 0.74 0.81 0.80 0.75 0.84 0.52 0.39 0.62 BMI 0.79 0.76 0.82 0.82 0.78 0.86 0.43 0.29 0.54 A m ci cum e ence 0.70 0.65 0.74 0.77 0.70 0.83 0.3 0.15 0.43 Wais ci c. elaxed 0.66 0.60 0.70 0.72 0.64 0.78 0.22 0.06 0.36 Wais ci c. sucking 0.62 0.56 0.67 0.68 0.59 0.75 0.28 0.14 0.42 K. 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The many aces o pleio opy. T ends Gene . 29, 66–73 (2013). 35. Tickle C. How he emb yo makes a limb: de e mina ion, pola i y and iden i y. J. Ana . 227:418–430 (2015). ACKNOWLEDGEMENTS KS and JK a e wo king in he BETTER4U p ojec . The BETTER4U p ojec has ecei ed unding om he Eu opean Union’s Ho izon Eu ope Resea ch and Inno a ion p og am unde G an Ag eemen #101080117, by UK Resea ch and Inno a ion (UKRI) unde he UK go e nmen ’s Ho izon Eu ope unding gua an ee (g an #10093560 o Queen Ma y Uni e si y o London and #10106435 o Bo n in B ad o d) and om he Swiss S a e Sec e a ia o Educa ion, Resea ch and Inno a ion (SERI). Views and opinions exp essed a e, howe e , hose o he au ho (s) only and do no necessa ily eflec hose o he Eu opean Union. AUTHOR CONTRIBUTIONS K.S., R.F.K. and M.M. designed he s udy. R.F.K., G.I.R. and M.M. collec ed he da a. K.S. conduc ed he analyses and w o e he fi s d a . R.S. helped in s a is ical analyses. K.S., R.F.K., A.J., R.S., G.I.R., J.K. and M.M. pa icipa ed in he in e p e a ion o da a. R.F.K., A.J., R.S., G.I.R., J.K. and M.M. e ised he manusc ip o impo an in ellec ual con en . All au ho s app o ed he final e sion o he manusc ip . FUNDING Open Access unding p o ided by Uni e si y o Helsinki (including Helsinki Uni e si y Cen al Hospi al). COMPETING INTERESTS The au ho s decla e no compe ing in e es s. CONSENT STATEMENT Pa icipan s ga e hei in o med consen when pa icipa ing in he s udy. All p ocedu es con ibu ing o his wo k comply wi h he e hical s anda ds o he ele an na ional and ins i u ional commi ees on human expe imen a ion and wi h he Helsinki Decla a ion o 1975, as e ised in 2008. The Uni e si y o Minneso a Ins i u ional Re iew Boa d (IRB) app o ed he s udy (STUDY00019239). ADDITIONAL INFORMATION Supplemen a y in o ma ion The online e sion con ains supplemen a y ma e ial a ailable a h ps://doi.o g/10.1038/s41390-025-04259-8. 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