PONE-D-22-15006Population History and Genome Wide Association Studies of Birth Weight in a Native High Altitude Ladakhi PopulationPLOS ONE

Dear Dr. Hilman,

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

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Reviewer #1: There are a few misprints in the text (line 78, 84).

The expression 'mechanistic study' is philosophically charged. It would be necessary to explain why you consider genomic studies as 'mechanistic',

The absence of genome wide significance for the variants should deserve a deeper discussion, especially in regard to future studies.

Reviewer #2: In this study Authors evaluated the genetic protective role in maintain an adequate birthweight at high altitude. The subject is of interest the study well designed so I would like to congratulate with Authors for their effort

My comments are

1) according to recent obstetrical ultrasonography FGR is defined by a Delphi consensus (Gordjin UOG 2016) on the basis of severity of growth restriction (i.e. < 3 centile) or association of a birthweight < 10 and concomitant Doppler changes in fetal hemodynamics. Since I guess that Doppler data analysis are not available in the study population Authors should include a sub analysis of newborn with a birthweight < 3 to show whether their hypothesis fits also in such subjects

2)it is not clear how Authors controlled for other potential confounding variables that influence fetal growth such as alimentation, associated maternal diseases occurring in pregnancy, anemia, …

3)I suggest adding a table sub grouping women according to the ethnicity (Tibetan and Ladakhi) and performing an univariate analysis of maternal and obstetrical characteristics

4)the limitations of the study should be reported

Reviewer #3: The study is the first to analyze the genetic fetal growth protection at a high altitude.

The study is of great interest and is well designed. The Authors should be congratulated for this complex research.

Comments:

1. Since birth weight is an important parameter of the study, a better specification of Fetal Growth Restriction with ultrasound during pregnancy according to the Delphi consensus and its association with the birthweight could be included, if available.

2. Since fetal development is strictly linked to the maternal environment (nutrition, physical activity, individual and community stress) and not only to the altitude considered in the study and since mothers completed a comprehensive questionnaire of their pregnancy history, it would be interesting to make one or more tables showing the data.

It should include also the relevant medical history, when present.

3. It would be interesting to compare different ethnicities and maternal medical and obstetrical histories.

4. The limitations of the study should be better presented.

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Reviewer #1: Yes: Bernardino Fantini

Reviewer #2: Yes: Giuseppe Rizzo

Reviewer #3: No

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Population History and Genome Wide Association Studies of Birth Weight in a Native High Altitude Ladakhi Population

PONE-D-22-15006R1

Dear Dr. Hillmann,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Giuseppe Novelli

Academic Editor

PLOS ONE

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